isolating-primary-melanocyte-like-cells-from-the-mouse-heart

Isolating Primary Melanocyte-like Cells from the Mouse Heart

We identified a novel population of melanocyte-like cells (also known as cardiac melanocytes) in the hearts of mice and humans that contribute to atrial ...

vascular-casting-adult-early-postnatal-mouse-lungs-for-micro-ct

Vascular Casting of Adult and Early Postnatal Mouse Lungs for Micro-CT Imaging

Blood vessels form intricate networks in 3-dimensional space. Consequently, it is difficult to visually appreciate how vascular networks interact and ...

University of Pennsylvania 

National Institutes of Health

Changes in serum folate concentrations following voluntary food fortification in Australia.

Cardiac-specific deletion of the murine gene (Cdh2) encoding the cell adhesion molecule, N-cadherin, results in disassembly of the intercalated disc (ICD) structure and sudden arrhythmic death. Connexin 43 (Cx43)-containing gap junctions are significantly reduced in the heart after depleting N-cadherin, therefore we hypothesized that animals expressing half the normal levels of N-cadherin would exhibit an intermediate phenotype. We examined the effect of N-cadherin haploinsufficiency on Cx43 expression and susceptibility to induced arrhythmias in mice either wild-type or heterozygous for the Cx43 (Gja1)-null allele. An increase in hypophosphorylated Cx43 accompanied by a modest decrease in total Cx43 protein levels was observed in the N-cadherin heterozygous mice. Consistent with these findings N-cadherin heterozygotes exhibited increased susceptibility to ventricular arrhythmias compared to wild-type mice. Quantitative immunofluorescence microscopy revealed a reduction in size of large Cx43-containing plaques in the N-cadherin heterozygous animals compared to wild-type. Gap junctions were further decreased in number and size in the N-cad/Cx43 compound heterozygous mice with increased arrhythmic susceptibility compared to the single mutants. The scaffold protein, ZO-1, was reduced at the ICD in N-cadherin heterozygous cardiomyocytes providing a possible explanation for the reduction in Cx43 plaque size. These data provide further support for the intimate relationship between N-cadherin and Cx43 in the heart, and suggest that germline mutations in the human N-cadherin (Cdh2) gene may predispose patients to increased risk of cardiac arrhythmias.

N-cadherin haploinsufficiency affects cardiac gap junctions and arrhythmic susceptibility.

Atrial fibrosis influences the development of atrial fibrillation (AF), particularly in the setting of structural heart disease where angiotensin-inhibition is partially effective for reducing atrial fibrosis and AF. Histone-deacetylase inhibition reduces cardiac hypertrophy and fibrosis, so we sought to determine if the HDAC inhibitor trichostatin A (TSA) could reduce atrial fibrosis and arrhythmias. Mice over-expressing homeodomain-only protein (HopX(Tg)), which recruits HDAC activity to induce cardiac hypertrophy were investigated in 4 groups (aged 14-18 weeks): wild-type (WT), HopX(Tg), HopX(Tg) mice treated with TSA for 2 weeks (TSA-HopX) and wild-type mice treated with TSA for 2 weeks (TSA-WT). These groups were characterized using invasive electrophysiology, atrial fibrosis measurements, atrial connexin immunocytochemistry and myocardial angiotensin II measurements. Invasive electrophysiologic stimulation, using the same attempts in each group, induced more atrial arrhythmias in HopX(Tg) mice (48 episodes in 13 of 15 HopX(Tg) mice versus 5 episodes in 2 of 15 TSA-HopX mice, P<0.001; versus 9 episodes in 2 of 15 WT mice, P<0.001; versus no episodes in any TSA-WT mice, P<0.001). TSA reduced atrial arrhythmia duration in HopX(Tg) mice (1307+/-289 ms versus 148+/-110 ms, P<0.01) and atrial fibrosis (8.1+/-1.5% versus 3.9+/-0.4%, P<0.001). Atrial connexin40 was lower in HopX(Tg) compared to WT mice, and TSA normalized the expression and size distribution of connexin40 gap junctions. Myocardial angiotensin II levels were similar between WT and HopX(Tg) mice (76.3+/-26.0 versus 69.7+/-16.6 pg/mg protein, P=NS). Therefore, it appears HDAC-inhibition reverses atrial fibrosis, connexin40 remodeling and atrial arrhythmia vulnerability independent of angiotensin II in cardiac hypertrophy.

Histone-deacetylase inhibition reverses atrial arrhythmia inducibility and fibrosis in cardiac hypertrophy independent of angiotensin.

Nonsteroidal anti-inflammatory drugs selective for inhibition of COX-2 increase heart failure and elevate blood pressure. The COX-2 gene was floxed and crossed into merCremer mice under the alpha-myosin heavy-chain promoter. Tamoxifen induced selective deletion of COX-2 in cardiomyocytes depressed cardiac output, and resulted in weight loss, diminished exercise tolerance, and enhanced susceptibility to induced arrhythmogenesis. The cardiac dysfunction subsequent to pressure overload recovered progressively in the knockouts coincident with increasing cardiomyocyte hypertrophy and interstitial and perivascular fibrosis. Inhibition of COX-2 in cardiomyocytes may contribute to heart failure in patients receiving nonsteroidal anti-inflammatory drugs specific for inhibition of COX-2.

Cardiomyocyte cyclooxygenase-2 influences cardiac rhythm and function.

&#x5FC3;&#x623F;&#x7EA4;&#x98A4;&#x662F;&#x6700;&#x5E38;&#x89C1;&#x7684;&#x4E34;&#x5E8A;&#x5FC3;&#x5F8B;&#x5931;&#x5E38;&#x3002;&#x5B83;&#x901A;&#x5E38;&#x7531;&#x65E9;&#x640F;&#x5F15;&#x8D77;&#x80BA;&#x9759;&#x8109;&#x548C;&#x5FC3;&#x623F;&#xFF0C;&#x4F46;&#x6E90;&#x548C;&#x8FD9;&#x4E9B;&#x8282;&#x62CD;&#x7684;&#x673A;&#x5236;&#x4ECD;&#x4E0D;&#x6E05;&#x695A;&#x3002;&#x9ED1;&#x8272;&#x7D20;&#x5408;&#x6210;&#x9176;&#x4F53; tautomerase (DCT) &#x88AB;&#x53C2;&#x4E0E;&#x7EC6;&#x80DE;&#x5185;&#x9499;&#x79BB;&#x5B50;&#x548C;&#x6D3B;&#x6027;&#x7269;&#x79CD;&#x8C03;&#x8282;&#x9ED1;&#x7D20;&#x7EC6;&#x80DE;&#x4E2D;&#x3002;&#x65E2;&#x7136;&#x65F6;&#x5F02;&#x5E38;&#x7684;&#x7EC6;&#x80DE;&#x5185;&#x9499;&#x79BB;&#x5B50;&#x548C;&#x6D3B;&#x6027;&#x7269;&#x79CD;&#x5DF2;&#x8FF0;&#x5FC3;&#x623F;&#x98A4;&#x52A8;&#x60A3;&#x8005;&#xFF0C;&#x6211;&#x4EEC;&#x8C03;&#x67E5;&#x7684; DCT &#x5728;&#x6B64;&#x8FC7;&#x7A0B;&#x4E2D;&#x7684;&#x4F5C;&#x7528;&#x3002;&#x5728;&#x8FD9;&#x91CC;&#xFF0C;&#x6211;&#x4EEC;&#x7684;&#x7279;&#x70B9;&#x662F;&#x552F;&#x4E00; DCT &#x8868;&#x793A;&#x5355;&#x5143;&#x683C;&#x4EBA;&#x53E3;&#x5185;&#x586B;&#x5145;&#x80BA;&#x9759;&#x8109;&#x3001; &#x5FC3;&#x623F;&#x3001; &#x623F;&#x5BA4;&#x7684;&#x5C0F;&#x9F20;&#x548C;&#x4EBA;&#x7C7B;&#x7684;&#x5FC3;&#x4E2D;&#x3002;&#x8868;&#x8FBE;&#x8C31;&#x8868;&#x660E;&#x8FD9;&#x4E00;&#x4EBA;&#x53E3;&#x8868;&#x793A;&#x80BE;&#x4E0A;&#x817A;&#x7D20;&#x80FD;&#x548C;&#x6BD2;&#x8548;&#x78B1;&#x53D7;&#x4F53;&#xFF0C;&#x5E76;&#x663E;&#x793A;&#x4E0D;&#x540C;&#x7684;&#x76AE;&#x80A4;&#x9ED1;&#x7D20;&#x7EC6;&#x80DE;&#x7684;&#x8F6C;&#x5F55;&#x914D;&#x7F6E;&#x6587;&#x4EF6;&#x3002;&#x6210;&#x5E74;&#x5C0F;&#x9F20;&#x7F3A;&#x4E4F; DCT &#x663E;&#x793A;&#x6B63;&#x5E38;&#x5FC3;&#x810F;&#x7684;&#x53D1;&#x5C55;&#xFF0C;&#x4F46;&#x5BF9;&#x623F;&#x6027;&#x5FC3;&#x5F8B;&#x5931;&#x5E38;&#x7684;&#x654F;&#x611F;&#x6027;&#x589E;&#x52A0;&#x3002;&#x539F;&#x53D1;&#x6027;&#x5FC3;&#x810F;&#x9ED1;&#x7D20;&#x7EC6;&#x80DE;&#x6837;&#x7EC6;&#x80DE;&#x88AB;&#x6FC0;&#x53D1;&#xFF0C;&#x548C;&#x90A3;&#x4E9B;&#x7F3A;&#x4E4F; DCT &#x663E;&#x793A;&#x4E0E;&#x65E9;&#x671F;&#x540E;&#x9664;&#x6781;&#x5EF6;&#x957F;&#x590D;&#x6781;&#x3002;&#x6B64;&#x5916;&#xFF0C;&#x4E0E;&#x916A;&#x6C28;&#x9178;&#x6FC0;&#x9176;&#x53D7;&#x4F53; Kit &#x57FA;&#x56E0;&#x7A81;&#x53D8;&#x5C0F;&#x9F20;&#x7F3A;&#x4E4F;&#x5FC3;&#x810F;&#x9ED1;&#x7D20;&#x7EC6;&#x80DE;&#x6837;&#x7EC6;&#x80DE;&#xFF0C;&#x4E0D;&#x5F00;&#x53D1; DCT &#x7F3A;&#x5E2D;&#x7684;&#x623F;&#x6027;&#x5FC3;&#x5F8B;&#x5931;&#x5E38;&#x3002;&#x8FD9;&#x4E9B;&#x6570;&#x636E;&#x8868;&#x660E;&#x5728;&#x4E2D;&#x5EAD;&#x7684;&#x9ED1;&#x7D20;&#x7EC6;&#x80DE;&#x6837;&#x7EC6;&#x80DE;&#x529F;&#x80FD;&#x969C;&#x788D;&#x548C;&#x80BA;&#x9759;&#x8109;&#x53EF;&#x80FD;&#x6709;&#x52A9;&#x4E8E;&#x623F;&#x6027;&#x5FC3;&#x5F8B;&#x5931;&#x5E38;&#x3002;

&#x9ED1;&#x7D20;&#x7EC6;&#x80DE;&#x6837;&#x7EC6;&#x80DE;&#x5728;&#x5FC3;&#x810F;&#x548C;&#x80BA;&#x9759;&#x8109;&#x5BF9;&#x623F;&#x6027;&#x5FC3;&#x5F8B;&#x5931;&#x5E38;&#x89E6;&#x53D1;&#x5668;&#x4F5C;&#x51FA;&#x8D21;&#x732E;&#x3002;

Atrial fibrillation is the most common clinical cardiac arrhythmia. It is often initiated by ectopic beats arising from the pulmonary veins and atrium, but the source and mechanism of these beats remains unclear. The melanin synthesis enzyme dopachrome tautomerase (DCT) is involved in intracellular calcium and reactive species regulation in melanocytes. Given that dysregulation of intracellular calcium and reactive species has been described in patients with atrial fibrillation, we investigated the role of DCT in this process. Here, we characterize a unique DCT-expressing cell population within murine and human hearts that populated the pulmonary veins, atria, and atrioventricular canal. Expression profiling demonstrated that this population expressed adrenergic and muscarinic receptors and displayed transcriptional profiles distinct from dermal melanocytes. Adult mice lacking DCT displayed normal cardiac development but an increased susceptibility to atrial arrhythmias. Cultured primary cardiac melanocyte-like cells were excitable, and those lacking DCT displayed prolonged repolarization with early afterdepolarizations. Furthermore, mice with mutations in the tyrosine kinase receptor Kit lacked cardiac melanocyte-like cells and did not develop atrial arrhythmias in the absence of DCT. These data suggest that dysfunction of melanocyte-like cells in the atrium and pulmonary veins may contribute to atrial arrhythmias.

Melanocyte-like cells in the heart and pulmonary veins contribute to atrial arrhythmia triggers.

La fibrillation auriculaire est l&#x26;#39;arythmie la plus fr&#xE9;quente cardiaque clinique. Il est souvent initi&#xE9;e par des battements ectopiques d&#xE9;coulant des veines pulmonaires et l&#x26;#39;atrium, mais la source et le m&#xE9;canisme de ces battements reste incertaine. La synth&#xE8;se de l&#x26;#39;enzyme de m&#xE9;lanine dopachrome tautom&#xE9;rase (DCT) est impliqu&#xE9;e dans la r&#xE9;gulation du calcium intracellulaire et les esp&#xE8;ces r&#xE9;actives dans les m&#xE9;lanocytes. &#xC9;tant donn&#xE9; que la d&#xE9;r&#xE9;gulation du calcium intracellulaire et les esp&#xE8;ces r&#xE9;actives a &#xE9;t&#xE9; d&#xE9;crite chez les patients atteints de fibrillation auriculaire, nous avons &#xE9;tudi&#xE9; le r&#xF4;le de la DCT dans ce processus. Ici, nous caract&#xE9;risons une population de cellules uniques DCT-exprimant dans les coeurs murins et humains qui ont peupl&#xE9; les veines pulmonaires, les atriums, et du canal auriculo-ventriculaire. Profilage de l&#x26;#39;expression a montr&#xE9; que cette population a exprim&#xE9; r&#xE9;cepteurs adr&#xE9;nergiques et muscariniques et affich&#xE9;es profils transcriptionnels distincts &#xE0; partir de m&#xE9;lanocytes dermiques. Les souris adultes qui n&#x26;#39;ont pas affich&#xE9; DCT normale d&#xE9;veloppement cardiaque, mais une susceptibilit&#xE9; accrue aux arythmies auriculaires. De culture primaire cardiaques m&#xE9;lanocytes comme les cellules &#xE9;taient excitable, et ceux qui n&#x26;#39;ont pas affich&#xE9; la repolarisation DCT prolong&#xE9; avec postd&#xE9;polarisations d&#xE9;but. En outre, les souris porteuses de mutations dans le r&#xE9;cepteur tyrosine kinase Kit manquait cardiaques m&#xE9;lanocytes comme les cellules et ne d&#xE9;veloppent pas d&#x26;#39;arythmie auriculaire en l&#x26;#39;absence de DCT. Ces donn&#xE9;es sugg&#xE8;rent que le dysfonctionnement des m&#xE9;lanocytes, comme les cellules dans l&#x26;#39;atrium et les veines pulmonaires peuvent contribuer &#xE0; des arythmies auriculaires.

M&#xE9;lanotrope comme les cellules du c&#x153;ur et les veines pulmonaires Contribuer &#xE0; D&#xE9;clencheurs arythmie auriculaire

Vorhofflimmern ist die h&auml;ufigste klinische Herzrhythmusst&ouml;rungen. Es wird oft durch ektopische Schl&auml;ge aus den Lungenvenen und Atrium, aber die Quelle initiiert und Mechanismus diese Beats bleibt unklar. Die Melanin Synthese Enzyms Dopachrom-Tautomerase (DCT) ist intrazellul&auml;re Calcium und reaktiven Spezies Verordnung in Melanozyten beteiligt. Angesichts der Tatsache, dass bei Patienten mit Vorhofflimmern Dysregulation intrazellul&auml;re Calcium-und reaktiven Spezies beschrieben wurde, untersuchten wir die Rolle der DCT in diesem Prozess. Hier zeichnen wir eine einzigartige DCT-Ausdr&uuml;cken Zellpopulation in murinen und menschlichen Herzen, die die Lungenvenen, Atrien und Atrioventrikul&auml;rer Kanal aufgef&uuml;llt. Expression profiling gezeigt, dass diese Population ausgedr&uuml;ckt adrenerge und muskarinische Rezeptoren unterscheidet dermale Melanozyten transkriptionelle Profile angezeigt. Erwachsene M&auml;usen fehlt DCT angezeigt normalen kardialen Entwicklung aber eine erh&ouml;hte Anf&auml;lligkeit f&uuml;r atriale Arrhythmien. Kultivierte prim&auml;re Melanozyten-wie in der Herzzellen waren erregbar, und diejenigen fehlt DCT angezeigt verl&auml;ngerte Repolarisation mit fr&uuml;hen Afterdepolarizations. Dar&uuml;ber hinaus M&auml;use mit Mutationen in der Tyrosin-Kinase-Rezeptor Kit fehlte Melanozyten-wie Herzzellen und atriale Arrhythmien ohne DCT nicht entwickeln. Diese Daten legen nahe, dass Funktionsst&ouml;rungen der Melanozyten-wie Zellen im Atrium und Lungenvenen kann dazu beitragen, atriale Arrhythmien.

Melanozyten-&auml;hnlichen Zellen in das Herz und die Lungenvenen dazu beitragen, Vorhofflimmern Arrhythmie-Trigger.

La fibrillazione atriale &egrave; la pi&ugrave; comune aritmia cardiaca clinica. &Egrave; spesso iniziato da battiti ectopici derivanti dalle vene polmonari e l&#39;atrio, ma la fonte e il meccanismo di queste battute rimane poco chiaro. La sintesi di melanina enzima tautomerase dopachrome (DCT) &egrave; coinvolto nel calcio intracellulare e regolamento specie reattive in melanociti. Dato che la disregolazione del calcio intracellulare e specie reattive &egrave; stata descritta in pazienti con fibrillazione atriale, abbiamo studiato il ruolo del DCT in questo processo. Qui, ci caratterizzano un&#39;unica popolazione cellulare DCT-esprimere all&#39;interno di cuori murine e umane che hanno popolato le vene polmonari, atri e canale atrioventricolare. Delineamento di espressione hanno dimostrato che questa popolazione espressi recettori adrenergici e muscarinici e visualizzato transcriptional profili distinti dai melanociti dermici. Topi adulti privi di DCT visualizzato normale sviluppo cardiaco ma un aumento della suscettibilit&agrave; alle aritmie atriali. Colture primarie cardiache melanocita-come le cellule sono eccitabili, e quelli mancano DCT visualizzato ripolarizzazione prolungata con early afterdepolarizations. Inoltre, topi con mutazioni nel recettore tirosina chinasi Kit mancavano melanocita-come cellule cardiache e non ha fatto sviluppare aritmie atriali in assenza di DCT. Questi dati suggeriscono che la disfunzione dei melanociti-come le cellule dell&#39;atrio e vene polmonari pu&ograve; contribuire ad aritmie atriali.

Melanocita-come le cellule nel cuore e vene polmonari contribuiscono a trigger di aritmia atriale.

&#x5FC3;&#x623F;&#x7D30;&#x52D5;&#x306F;&#x3001;&#x6700;&#x3082;&#x4E00;&#x822C;&#x7684;&#x306A;&#x81E8;&#x5E8A;&#x4E0D;&#x6574;&#x8108;&#x3067;&#x3059;&#x3002;&#x305D;&#x308C;&#x306F;&#x3057;&#x3070;&#x3057;&#x3070;&#x80BA;&#x9759;&#x8108;&#x3068;&#x5FC3;&#x623F;&#x304B;&#x3089;&#x767A;&#x751F;&#x3059;&#x308B;&#x7570;&#x6240;&#x6027;&#x62CD;&#x306B;&#x3088;&#x3063;&#x3066;&#x958B;&#x59CB;&#x3055;&#x308C;&#x305F;&#x304C;&#x3001;&#x3053;&#x308C;&#x3089;&#x306E;&#x30D3;&#x30FC;&#x30C8;&#x306E;&#x30BD;&#x30FC;&#x30B9;&#x3068;&#x30E1;&#x30AB;&#x30CB;&#x30BA;&#x30E0;&#x306F;&#x4E0D;&#x660E;&#x306E;&#x307E;&#x307E;&#x3067;&#x3059;&#x3002;&#x30E1;&#x30E9;&#x30CB;&#x30F3;&#x5408;&#x6210;&#x9175;&#x7D20;&#x30C9;&#x30D1;&#x30AF;&#x30ED;&#x30E0;&#x306E;tautomerase&#xFF08;DCT&#xFF09;&#x306F;&#x3001;&#x7D30;&#x80DE;&#x5185;&#x30AB;&#x30EB;&#x30B7;&#x30A6;&#x30E0;&#x3068;&#x30E1;&#x30E9;&#x30CE;&#x30B5;&#x30A4;&#x30C8;&#x306E;&#x53CD;&#x5FDC;&#x7A2E;&#x306E;&#x8ABF;&#x7BC0;&#x306B;&#x95A2;&#x4E0E;&#x3057;&#x3066;&#x3044;&#x308B;&#x3002;&#x7D30;&#x80DE;&#x5185;&#x306E;&#x30AB;&#x30EB;&#x30B7;&#x30A6;&#x30E0;&#x3068;&#x53CD;&#x5FDC;&#x7A2E;&#x306E;&#x8ABF;&#x7BC0;&#x4E0D;&#x5168;&#x306F;&#x5FC3;&#x623F;&#x7D30;&#x52D5;&#x60A3;&#x8005;&#x306B;&#x8A18;&#x8F09;&#x3055;&#x308C;&#x3066;&#x3044;&#x308B;&#x3053;&#x3068;&#x3092;&#x8003;&#x3048;&#x308B;&#x3068;&#x3001;&#x6211;&#x3005;&#x306F;&#x3053;&#x306E;&#x30D7;&#x30ED;&#x30BB;&#x30B9;&#x3067;&#x306F;DCT&#x306E;&#x5F79;&#x5272;&#x3092;&#x8ABF;&#x3079;&#x305F;&#x3002;&#x3053;&#x3053;&#x3067;&#x306F;&#x3001;&#x80BA;&#x9759;&#x8108;&#x3001;&#x5FC3;&#x623F;&#x3001;&#x623F;&#x5BA4;&#x7BA1;&#x3092;&#x88C5;&#x7740;&#x3059;&#x308B;&#x3053;&#x3068;&#x3001;&#x30DE;&#x30A6;&#x30B9;&#x304A;&#x3088;&#x3073;&#x30D2;&#x30C8;&#x306E;&#x5FC3;&#x306E;&#x4E2D;&#x3067;&#x30E6;&#x30CB;&#x30FC;&#x30AF;&#x306A;DCT&#x3092;&#x767A;&#x73FE;&#x3059;&#x308B;&#x7D30;&#x80DE;&#x96C6;&#x56E3;&#x3092;&#x7279;&#x5FB4;&#x4ED8;&#x3051;&#x308B;&#x3002;&#x767A;&#x73FE;&#x30D7;&#x30ED;&#x30D5;&#x30A1;&#x30A4;&#x30EA;&#x30F3;&#x30B0;&#x306F;&#x3001;&#x3053;&#x306E;&#x4EBA;&#x53E3;&#x306F;&#x771F;&#x76AE;&#x30E1;&#x30E9;&#x30CE;&#x30B5;&#x30A4;&#x30C8;&#x3068;&#x306F;&#x7570;&#x306A;&#x308B;&#x30A2;&#x30C9;&#x30EC;&#x30CA;&#x30EA;&#x30F3;&#x304A;&#x3088;&#x3073;&#x30E0;&#x30B9;&#x30AB;&#x30EA;&#x30F3;&#x53D7;&#x5BB9;&#x4F53;&#x3068;&#x8868;&#x793A;&#x3055;&#x308C;&#x305F;&#x8EE2;&#x5199;&#x30D7;&#x30ED;&#x30D5;&#x30A1;&#x30A4;&#x30EB;&#x3092;&#x8868;&#x660E;&#x3057;&#x305F;&#x3053;&#x3068;&#x3092;&#x660E;&#x3089;&#x304B;&#x306B;&#x3057;&#x305F;&#x3002; DCT&#x3092;&#x6B20;&#x3044;&#x305F;&#x6210;&#x4F53;&#x30DE;&#x30A6;&#x30B9;&#x3067;&#x306F;&#x3001;&#x5FC3;&#x623F;&#x6027;&#x4E0D;&#x6574;&#x8108;&#x3092;&#x6B63;&#x5E38;&#x306A;&#x5FC3;&#x81D3;&#x306E;&#x958B;&#x767A;&#x304C;&#x5897;&#x52A0;&#x3057;&#x305F;&#x611F;&#x53D7;&#x6027;&#x304C;&#x8868;&#x793A;&#x3055;&#x308C;&#x307E;&#x3059;&#x3002;&#x57F9;&#x990A;&#x3055;&#x308C;&#x305F;&#x539F;&#x767A;&#x6027;&#x5FC3;&#x81D3;&#x30E1;&#x30E9;&#x30CB;&#x30F3;&#x7D30;&#x80DE;&#x69D8;&#x7D30;&#x80DE;&#x306F;&#x8208;&#x596E;&#x3057;&#x305F;&#x3057;&#x3001;&#x305D;&#x308C;&#x3089;&#x306E;&#x6B20;&#x3051;&#x3066;&#x3044;&#x308B;DCT&#x306F;&#x3001;&#x65E9;&#x671F;afterdepolarizations&#x3068;&#x306E;&#x9577;&#x671F;&#x306E;&#x518D;&#x5206;&#x6975;&#x304C;&#x8868;&#x793A;&#x3055;&#x308C;&#x307E;&#x3057;&#x305F;&#x3002;&#x3055;&#x3089;&#x306B;&#x3001;&#x30C1;&#x30ED;&#x30B7;&#x30F3;&#x30AD;&#x30CA;&#x30FC;&#x30BC;&#x53D7;&#x5BB9;&#x4F53;&#x30AD;&#x30C3;&#x30C8;&#x306E;&#x5909;&#x7570;&#x3092;&#x6301;&#x3064;&#x30DE;&#x30A6;&#x30B9;&#x306F;&#x3001;&#x5FC3;&#x81D3;&#x306E;&#x30E1;&#x30E9;&#x30CB;&#x30F3;&#x7D30;&#x80DE;&#x69D8;&#x7D30;&#x80DE;&#x3092;&#x6B20;&#x3044;&#x3066;&#x3044;&#x305F;&#x3068;DCT&#x306E;&#x4E0D;&#x5728;&#x4E0B;&#x3067;&#x5FC3;&#x623F;&#x6027;&#x4E0D;&#x6574;&#x8108;&#x3092;&#x958B;&#x767A;&#x3057;&#x3066;&#x3044;&#x307E;&#x305B;&#x3093;&#x3067;&#x3057;&#x305F;&#x3002;&#x3053;&#x308C;&#x3089;&#x306E;&#x30C7;&#x30FC;&#x30BF;&#x306F;&#x3001;&#x5FC3;&#x623F;&#x3068;&#x80BA;&#x9759;&#x8108;&#x306E;&#x30E1;&#x30E9;&#x30CB;&#x30F3;&#x7D30;&#x80DE;&#x69D8;&#x7D30;&#x80DE;&#x306E;&#x6A5F;&#x80FD;&#x4E0D;&#x5168;&#x306F;&#x5FC3;&#x623F;&#x6027;&#x4E0D;&#x6574;&#x8108;&#x306B;&#x5BC4;&#x4E0E;&#x3059;&#x308B;&#x3053;&#x3068;&#x3092;&#x793A;&#x5506;&#x3057;&#x3066;&#x3044;&#x308B;&#x3002;

&#x5FC3;&#x81D3;&#x3068;&#x80BA;&#x9759;&#x8108;&#x306E;&#x30E1;&#x30E9;&#x30CB;&#x30F3;&#x7D30;&#x80DE;&#x69D8;&#x7D30;&#x80DE;&#x306F;&#x5FC3;&#x623F;&#x6027;&#x4E0D;&#x6574;&#x8108;&#x306E;&#x30C8;&#x30EA;&#x30AC;&#x30FC;&#x306B;&#x8CA2;&#x732E;

&#xC2EC; &#xBC29; &#xC138; &#xB3D9;&#xACFC; &#xAC00;&#xC7A5; &#xC77C;&#xBC18;&#xC801;&#xC778; &#xC784;&#xC0C1; &#xC2EC;&#xC7A5; &#xBD80;&#xC815;&#xB9E5; &#xC774;&#xB2E4;. &#xC885;&#xC885; &#xD3D0; &#xC815; &#xB9E5; &#xBC0F; &#xC544; &#xD2B8;&#xB9AC; &#xC6C0;, &#xD558;&#xC9C0;&#xB9CC; &#xC18C;&#xC2A4;&#xC5D0;&#xC11C; &#xBC1C;&#xC0DD; &#xD558;&#xB294; &#xC18C;&#xC131; &#xBC15;&#xB3D9;&#xC5D0; &#xC758;&#xD574; &#xC2DC;&#xC791; &#xB418; &#xACE0; &#xC774;&#xB7EC;&#xD55C; &#xBC15;&#xB3D9;&#xC758; &#xBA54;&#xCEE4;&#xB2C8;&#xC998;&#xC774; &#xBD88;&#xBD84;&#xBA85; &#xB0A8;&#xC544;. &#xBA5C; &#xB77C; &#xB2CC; &#xD569;&#xC131; &#xD6A8;&#xC18C; dopachrome tautomerase (DCT)&#xB294; &#xC138;&#xD3EC;&#xB0B4; &#xCE7C;&#xC298;&#xACFC; &#xBC18;&#xC751; &#xC885; &#xADDC;&#xC81C; melanocytes&#xC5D0; &#xCC38;&#xC5EC; &#xD558;&#xACE0;&#xC788;&#xB2E4;. &#xC138;&#xD3EC;&#xB0B4; &#xCE7C;&#xC298;&#xACFC; &#xBC18;&#xC751; &#xC885; dysregulation &#xC2EC; &#xBC29; &#xC138; &#xB3D9; &#xD658;&#xC790;&#xC5D0;&#xC11C; &#xC124;&#xBA85; &#xD558;&#xACE0;&#xC788;&#xB2E4;, &#xC6B0;&#xB9AC;&#xAC00;&#xC774; &#xACFC;&#xC815;&#xC5D0;&#xC11C; DCT&#xC758; &#xC5ED;&#xD560; &#xC870;&#xC0AC;. &#xC5EC;&#xAE30;&#xC5D0;&#xC11C;, &#xC6B0;&#xB9AC;&#xB294; &#xD3D0; &#xC815; &#xB9E5;, atria, &#xBC0F; atrioventricular &#xC6B4;&#xD558; &#xCC44;&#xC6CC;&#xC9C4; murine &#xC778;&#xAC04;&#xACFC; &#xB9C8;&#xC74C; &#xB0B4; &#xB3C5;&#xD2B9;&#xD55C; DCT &#xD45C;&#xD604; &#xC140; &#xC778;&#xAD6C; &#xD2B9;&#xC9D5;. &#xC774; &#xC778;&#xAD6C; &#xC544;&#xB4DC;&#xB808;&#xB0A0;&#xB9B0; &#xBC0F; muscarinic &#xC218;&#xC6A9; &#xCCB4;&#xB97C; &#xD45C;&#xD604; &#xD558; &#xACE0; &#xD53C;&#xBD80; melanocytes &#xB2E4;&#xB97C; transcriptional &#xD504;&#xB85C;&#xD544; &#xD45C;&#xC2DC; &#xC2DC;&#xC5F0; &#xC2DD; &#xD504;&#xB85C; &#xD30C;&#xC77C;&#xB9C1;. &#xC131;&#xC778; &#xC0DD;&#xC950; DCT &#xBD80;&#xC871; &#xD45C;&#xC2DC; &#xC2EC; &#xBD80;&#xC815;&#xB9E5;&#xC744; &#xC99D;&#xAC00; &#xC790;&#xD654; &#xC728; &#xD558;&#xC9C0;&#xB9CC; &#xC815;&#xC0C1;&#xC801;&#xC778; &#xC2EC;&#xC7A5; &#xBC1C;&#xB2EC;. &#xAD50;&#xC591;&#xB41C; &#xAE30;&#xBCF8; &#xC2EC;&#xC7A5; melanocyte &#xAC19;&#xC740; &#xC140; &#xACE0;&#xB974;&#xAE30;, &#xADF8;&#xB9AC;&#xACE0; DCT &#xBD80;&#xC871; &#xD45C;&#xC2DC; &#xB41C; &#xCD08;&#xAE30; afterdepolarizations&#xC640; &#xC7A5;&#xAE30;&#xAC04;&#xB41C; repolarization. &#xB610;&#xD55C;, &#xD2F0;&#xB85C;&#xC2E0; &#xD0A4; &#xB2C8; &#xC544; &#xC81C; &#xC218;&#xC6A9; &#xCCB4; &#xD0A4;&#xD2B8;&#xC5D0;&#xC5D0;&#xC11C; &#xB3CC;&#xC5F0;&#xBCC0;&#xC774;&#xC640; &#xC950; &#xC2EC;&#xC7A5; melanocyte &#xAC19;&#xC740; &#xC140;&#xC774; &#xBD80;&#xC871; &#xD558; &#xACE0; DCT&#xC758; &#xBD80;&#xC7AC;&#xC5D0; &#xC788;&#xB294; &#xC2EC; &#xBD80;&#xC815;&#xB9E5;&#xC744; &#xAC1C;&#xBC1C; &#xD558;&#xC9C0; &#xC54A;&#xC558;&#xB2E4;. &#xC774;&#xB7EC;&#xD55C; &#xB370;&#xC774;&#xD130; &#xC81C;&#xC548; melanocyte &#xAC19;&#xC740; &#xC140; &#xC548;&#xB9C8;&#xB2F9;&#xC5D0;&#xB294; &#xBD80;&#xC804; &#xBC0F; &#xD3D0; &#xC815; &#xB9E5; &#xC2EC; &#xBC29; &#xBD80;&#xC815;&#xB9E5;&#xC5D0; &#xAE30;&#xC5EC;&#xD560; &#xC218; &#xC788;&#xC2B5;&#xB2C8;&#xB2E4;.

&#xC2EC;&#xC7A5;&#xACFC; &#xD3D0; &#xD608;&#xAD00;&#xC5D0; melanocyte &#xAC19;&#xC740; &#xC140; &#xC2EC; &#xBC29; &#xBD80;&#xC815;&#xB9E5; &#xD2B8;&#xB9AC;&#xAC70;&#xC5D0; &#xAE30;&#xC5EC;.

La fibrilaci&#xF3;n auricular es la arritmia cardiaca m&#xE1;s com&#xFA;n cl&#xED;nico. A menudo se inicia latidos ect&#xF3;picos que surgen de las venas pulmonares y la aur&#xED;cula, pero la fuente y el mecanismo de estos tiempos sigue siendo poco clara. La enzima de la s&#xED;ntesis de melanina dopacromo tautomerasa (DCT) est&#xE1; involucrado en el calcio intracelular y la regulaci&#xF3;n de las especies reactivas en los melanocitos. Teniendo en cuenta que la desregulaci&#xF3;n del calcio intracelular y las especies reactivas se ha descrito en pacientes con fibrilaci&#xF3;n auricular, se investig&#xF3; el papel de la DCT en este proceso. En este sentido, caracterizar una &#xFA;nica DCT-que expresa la poblaci&#xF3;n de c&#xE9;lulas dentro de los corazones murinos y humanos que poblaron las venas pulmonares, las aur&#xED;culas, y el canal auriculoventricular. Perfiles de expresi&#xF3;n demostr&#xF3; que esta poblaci&#xF3;n expresaron los receptores adren&#xE9;rgicos y muscar&#xED;nicos y mostr&#xF3; un perfil transcripcional distintos de los melanocitos d&#xE9;rmicos. Los ratones adultos que carecen de DCT muestra el desarrollo card&#xED;aco normal, pero una mayor susceptibilidad a las arritmias auriculares. Cultivadas card&#xED;aco primario de melanocitos-c&#xE9;lulas fueron excitable, y los que carecen de DCT muestra la repolarizaci&#xF3;n prolongada con afterdepolarizations. Adem&#xE1;s, los ratones con mutaciones en el Kit de tirosina quinasa del receptor carec&#xED;a card&#xED;acas como las c&#xE9;lulas melanocitos y que no desarrollaron arritmias auriculares en la ausencia de DCT. Estos datos sugieren que la disfunci&#xF3;n de los melanocitos-c&#xE9;lulas similares en el atrio y las venas pulmonares puede contribuir a las arritmias auriculares.

Melanocito-como las c&#xE9;lulas en el coraz&#xF3;n y las venas pulmonares Contribuir a los factores desencadenantes arritmia auricular

&#x7EBF;&#x7C92;&#x4F53;&#x819C;&#x6F5C;&#x5728;&#x635F;&#x5931;&#x4E86;&#x751F;&#x547D;&#x7684;&#x4E25;&#x91CD;&#x540E;&#x679C;&#xFF0C;&#x5E76;&#x6709;&#x52A9;&#x4E8E;&#x8BB8;&#x591A;&#x4EBA;&#x7C7B;&#x75BE;&#x75C5;&#x5305;&#x62EC;&#x5FC3;&#x808C;&#x6897;&#x6B7B;&#x3001; &#x8111;&#x5352;&#x4E2D;&#x3001; &#x80BF;&#x7624;&#x3001; &#x795E;&#x7ECF;&#x53D8;&#x6027;&#x3002;&#x7136;&#x800C;&#xFF0C;&#x5C3D;&#x7BA1;&#x5B83;&#x7684;&#x7A81;&#x51FA;&#x548C;&#x7EC6;&#x80DE;&#x80FD;&#x91CF;&#x751F;&#x4EA7;&#x4E2D;&#x7684;&#x91CD;&#x8981;&#x6027;&#xFF0C;&#x5373;&#x8BBE;&#x7ACB;&#x4E86;&#x7EBF;&#x7C92;&#x4F53;&#x819C;&#x7535;&#x4F4D;&#x7684;&#x57FA;&#x672C;&#x673A;&#x5236;&#x4ECD;&#x4E0D;&#x6E05;&#x695A;&#x3002;&#x6211;&#x4EEC;&#x7684;&#x7814;&#x7A76;&#x9610;&#x660E;&#x590D;&#x6742;&#x4E8C;&#x9A71;&#x52A8;&#x7535;&#x5B50;&#x6D41;&#x662F;&#x7531;&#x5176;&#x4E2D;&#x7EBF;&#x7C92;&#x4F53;&#x819C;&#x6781;&#x5316;&#x5728;&#x7F3A;&#x6C27;&#x7684;&#x6761;&#x4EF6;&#x4E0B;&#x548C;&#x590D;&#x6742;&#x7684;&#x4E8C;&#x886C;&#x5E95;&#x7425;&#x73C0;&#x9178;&#x7684;&#x7F3A;&#x4E4F;&#x5BFC;&#x81F4;&#x53EF;&#x9006;&#x819C;&#x6F5C;&#x5728;&#x635F;&#x5931;&#x53EF;&#x7531;&#x4E01;&#x4E8C;&#x9178;&#x8865;&#x5145;&#x8FC5;&#x901F;&#x6062;&#x590D;&#x7684;&#x4E3B;&#x8981;&#x624B;&#x6BB5;&#x3002;&#x6211;&#x548C; F (0) F 1 ATP &#x5408;&#x6210;&#x9176;&#x6291;&#x5236;&#x7EBF;&#x7C92;&#x4F53;&#x590D;&#x5408;&#x4F53;&#x8BF1;&#x5BFC;&#x7EBF;&#x7C92;&#x4F53;&#x7684;&#x53BB;&#x6781;&#x5316;&#xFF0C;&#x662F;&#x72EC;&#x7ACB;&#x4E8E;&#x7EBF;&#x7C92;&#x4F53;&#x901A;&#x900F;&#x6027;&#x8F6C;&#x6362;&#x5B54;&#x3001; Bcl-2 &#xFF08;B &#x7EC6;&#x80DE;&#x6DCB;&#x5DF4;&#x7624; 2) &#x5BB6;&#x65CF;&#x86CB;&#x767D;&#x6216;&#x9AD8;&#x632F;&#x5E45;&#x80BF;&#x80C0;&#x548C;&#x65E0;&#x6CD5;&#x626D;&#x8F6C;&#x7684;&#x4E01;&#x4E8C;&#x9178;&#x3002;&#x91CD;&#x8981;&#x7684;&#x662F;&#xFF0C;&#x5728;&#x7F3A;&#x6C27;&#x6761;&#x4EF6;&#x4E0B;&#x7684;&#x4E01;&#x4E8C;&#x9178;&#x4EE3;&#x8C22;&#x6062;&#x590D;&#x819C;&#x7535;&#x4F4D;&#x548C; ATP &#x6C34;&#x5E73;&#x3002;&#x6B64;&#x5916;&#xFF0C;&#x4E8C;&#x4ECB;&#x5BFC;&#x7684;&#x590D;&#x6742;&#x7535;&#x5B50;&#x6D41;&#x4F9D;&#x8D56;&#x5141;&#x8BB8;&#x7EC6;&#x80DE;&#x7EBF;&#x7C92;&#x4F53;&#x75BE;&#x75C5;&#x60A3;&#x8005;&#x6CA1;&#x6709;&#x590D;&#x6742;&#x7684;&#x529F;&#x80FD;&#x4ECE;&#x6211;&#x7EF4;&#x6301;&#x7EBF;&#x7C92;&#x4F53;&#x819C;&#x7535;&#x4F4D;&#x6240;&#x4F20;&#x8FBE;&#x7684;&#x7EBF;&#x7C92;&#x4F53;&#x7ED3;&#x6784;&#x548C;&#x87AF;&#x5408;&#x6FC0;&#x52A8;&#x5242;&#x8BF1;&#x5BFC;&#x9499;&#x7C7B;&#x4F3C;&#x4E8E;&#x6B63;&#x5E38;&#x7EC6;&#x80DE;&#x7684;&#x80FD;&#x529B;&#x3002;&#x8FD9;&#x4E00;&#x53D1;&#x73B0;&#x662F;&#x91CD;&#x8981;&#x7684;&#x56E0;&#x4E3A;&#x5B83;&#x4F5C;&#x4E3A;&#x6709;&#x5438;&#x5F15;&#x529B;&#x7684;&#x6CBB;&#x7597;&#x7F3A;&#x6C27;&#x65F6;&#x4FDD;&#x6301;&#x7EBF;&#x7C92;&#x4F53;&#x529F;&#x80FD;&#x8BBE;&#x7F6E;&#x590D;&#x6742;&#x4E8C;&#x529F;&#x80FD;&#x4FDD;&#x5B58;&#x7684;&#x821E;&#x53F0;&#x3002;

&#x7EBF;&#x7C92;&#x4F53;&#x590D;&#x5408;&#x7269; II &#x53EF;&#x9632;&#x6B62;&#x7F3A;&#x6C27;&#x4F46;&#x4E0D;&#x662F;&#x9499;&#x548C;&#x6D46;&#x6DB2; Bcl-2 &#x86CB;&#x767D;&#x8BF1;&#x5BFC;&#x7EBF;&#x7C92;&#x4F53;&#x819C;&#x6F5C;&#x5728;&#x635F;&#x5931;&#x3002;

Mitochondrial membrane potential loss has severe bioenergetic consequences and contributes to many human diseases including myocardial infarction, stroke, cancer, and neurodegeneration. However, despite its prominence and importance in cellular energy production, the basic mechanism whereby the mitochondrial membrane potential is established remains unclear. Our studies elucidate that complex II-driven electron flow is the primary means by which the mitochondrial membrane is polarized under hypoxic conditions and that lack of the complex II substrate succinate resulted in reversible membrane potential loss that could be restored rapidly by succinate supplementation. Inhibition of mitochondrial complex I and F(0)F(1)-ATP synthase induced mitochondrial depolarization that was independent of the mitochondrial permeability transition pore, Bcl-2 (B-cell lymphoma 2) family proteins, or high amplitude swelling and could not be reversed by succinate. Importantly, succinate metabolism under hypoxic conditions restores membrane potential and ATP levels. Furthermore, a reliance on complex II-mediated electron flow allows cells from mitochondrial disease patients devoid of a functional complex I to maintain a mitochondrial membrane potential that conveys both a mitochondrial structure and the ability to sequester agonist-induced calcium similar to that of normal cells. This finding is important as it sets the stage for complex II functional preservation as an attractive therapy to maintain mitochondrial function during hypoxia.

Mitochondrial complex II prevents hypoxic but not calcium- and proapoptotic Bcl-2 protein-induced mitochondrial membrane potential loss.

Mitochondrial perte du potentiel de membrane a de graves cons&#xE9;quences bio&#xE9;nerg&#xE9;tiques et contribue &#xE0; de nombreuses maladies humaines, y compris l&#x26;#39;infarctus du myocarde, accident vasculaire c&#xE9;r&#xE9;bral, le cancer, et de la neurod&#xE9;g&#xE9;n&#xE9;rescence. Cependant, malgr&#xE9; son importance et son importance dans la production d&#x26;#39;&#xE9;nergie cellulaire, le m&#xE9;canisme de base selon lequel le potentiel de membrane mitochondriale est &#xE9;tabli reste incertaine. Nos &#xE9;tudes d&#x26;#39;&#xE9;lucider ce complexe flux d&#x26;#39;&#xE9;lectrons II-entra&#xEE;n&#xE9; est le principal moyen par lequel la membrane mitochondriale est polaris&#xE9;e dans des conditions hypoxiques et que le manque de la succinate II substrat complexe a entra&#xEE;n&#xE9; la perte membrane r&#xE9;versible potentiel qui pourrait &#xEA;tre restaur&#xE9;e rapidement par la suppl&#xE9;mentation en succinate. L&#x26;#39;inhibition de la complexe mitochondrial I et F (0) F (1)-ATP synthase d&#xE9;polarisation induite mitochondrial qui est ind&#xE9;pendant du pore de transition membranaire de la mitochondrie, prot&#xE9;ines de la famille Bcl-2 (cellules B lymphome 2), ou l&#x26;#39;amplitude de gonflement et ne pouvait pas &#xEA;tre invers&#xE9; par le succinate. Il est important, le m&#xE9;tabolisme du succinate dans des conditions hypoxiques r&#xE9;tablit les niveaux de potentiel de membrane et de l&#x26;#39;ATP. En outre, une d&#xE9;pendance &#xE0; l&#x26;#39;&#xE9;gard flux d&#x26;#39;&#xE9;lectrons complexe II &#xE0; m&#xE9;diation permet aux cellules de patients atteints de maladies mitochondriales d&#xE9;pourvue d&#x26;#39;un complexe fonctionnel I pour maintenir un potentiel de membrane mitochondriale qui transmet &#xE0; la fois une structure mitochondrial et la capacit&#xE9; &#xE0; s&#xE9;questrer le calcium induit par un agoniste similaire &#xE0; celle des cellules normales . Cette constatation est importante car elle ouvre la voie &#xE0; la pr&#xE9;servation II complexe fonctionnel en tant que th&#xE9;rapie attrayante pour maintenir la fonction mitochondriale durant l&#x26;#39;hypoxie.

Complexe mitochondrial II Emp&#xEA;che hypoxique, mais pas de calcium et pro-apoptotique Bcl-2 Protein-induite Perte mitochondrial Le potentiel de membrane

Mitochondriale Membran Verlustpotential hat schwere bioenergetische folgen und tr&auml;gt zu vielen menschlichen Krankheiten einschlie&szlig;lich Myokardinfarkt, Schlaganfall, Krebs und Neurodegeneration. Trotz seiner Bekanntheit und Bedeutung bei der zellul&auml;ren Energieproduktion bleibt der grundlegende Mechanismus, wobei die mitochondriale Membran potenzielle niedergelassen ist, jedoch unklar. Unsere Studien verdeutlichen, dass komplexe II-gesteuerte Elektronen flie&szlig;en ist das wichtigste Mittel, mit denen die mitochondriale Membran ist unter Hypoxie Bedingungen polarisiert und dass der Mangel an den Komplex II-Substrat-Succinat f&uuml;hrte reversible Membran Verlustpotential, die rasch von Succinat-Supplementierung wiederhergestellt werden konnten. Hemmung der mitochondrialen Komplex I und F F (0) 1-ATP-Synthase induzierte mitochondriale Depolarisation, die unabh&auml;ngig von der mitochondrialen Permeabilit&auml;t &Uuml;bergang Pore, Bcl-2 (B-Zell-Lymphom 2) Familie Proteine oder hoher Amplitude Schwellung und von Succinat nicht r&uuml;ckg&auml;ngig gemacht werden k&ouml;nnte. Wichtig ist, stellt das Succinat Stoffwechsel unter Hypoxie Bedingungen Membran potenzielle und ATP Niveaus. Dar&uuml;ber hinaus erm&ouml;glicht eine Abh&auml;ngigkeit von Komplex II-vermittelte Elektronen flie&szlig;en Zellen vom Mitochondriopathie Patienten frei von einem funktionalen Komplex ich weiterhin eine m&ouml;gliche mitochondriale Membran, die eine mitochondriale-Struktur und die F&auml;higkeit, induziert durch Agonisten Kalzium &auml;hnlich der normalen Zellen absondern vermittelt. Diese Erkenntnis ist wichtig, denn es setzt die B&uuml;hne f&uuml;r komplexe II funktionelle Erhaltung als attraktive Therapie mitochondriale Funktion w&auml;hrend Hypoxie zu halten.

Mitochondriale Komplex II verhindert Hypoxie aber nicht Kalzium- und Proapoptotischen Bcl-2 Protein-induzierte mitochondriale Membran Verlustpotential.

Perdita potenziale di membrana mitocondriale ha gravi conseguenze bioenergetiche e contribuisce a molte malattie umane, inclusi infarto del miocardio, ictus, cancro e neurodegenerazione. Tuttavia, nonostante il suo risalto e importanza nella produzione di energia cellulare, il meccanismo di base per cui &egrave; stabilito il potenziale di membrana mitocondriale rimane poco chiaro. I nostri studi delucidare che complesso flusso di elettroni II-driven &egrave; il mezzo principale con cui la membrana mitocondriale &egrave; polarizzata nelle circostanze hypoxic e che la mancanza del complesso succinato substrato II ha provocato perdita potenziale di membrana reversibile che potrebbe essere ripristinata rapidamente dalla supplementazione di succinato. Inibizione del complesso mitocondriale I e F (0) F (1)-ATP sintasi indotta depolarizzazione mitocondriale che &egrave; stato indipendente del poro di transizione di permeabilit&agrave; mitocondriale, famiglie proteine Bcl-2 (B-cell lymphoma 2) o gonfiore ad alta ampiezza e non potrebbe essere rovesciato da succinato. Importante, metabolismo succinato nelle circostanze hypoxic ripristina il potenziale di membrana e livelli di ATP. Inoltre, un affidamento sul flusso degli elettroni mediata II complesso permette alle cellule da pazienti con malattia mitocondriale privo di un complesso funzionale che per mantenere un potenziale di membrana mitocondriale che trasmette sia una struttura mitocondriale e la capacit&agrave; di sequestrare agonista-indotta calcio simile a quello delle cellule normali. Questa scoperta &egrave; importante come imposta la fase complessa conservazione funzionale II come un attraente terapia per mantenere la funzione mitocondriale durante l&#39;ipossia.

II complesso mitocondriale impedisce ipossico ma non calcio - e Miselli Bcl-2 proteina indotta mitocondriale della membrana potenziale perdita.

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&#x30DF;&#x30C8;&#x30B3;&#x30F3;&#x30C9;&#x30EA;&#x30A2;&#x8907;&#x5408;&#x4F53;II&#x306F;&#x3001;&#x4F4E;&#x9178;&#x7D20;&#x3067;&#x306F;&#x306A;&#x304F;&#x30AB;&#x30EB;&#x30B7;&#x30A6;&#x30E0;&#x3068;&#x30A2;&#x30DD;&#x30C8;&#x30FC;&#x30B7;&#x30B9;Bcl-2&#x30BF;&#x30F3;&#x30D1;&#x30AF;&#x8CEA;&#x306B;&#x3088;&#x3063;&#x3066;&#x8A98;&#x5C0E;&#x3055;&#x308C;&#x308B;&#x30DF;&#x30C8;&#x30B3;&#x30F3;&#x30C9;&#x30EA;&#x30A2;&#x819C;&#x96FB;&#x4F4D;&#x306E;&#x640D;&#x5931;&#x3092;&#x9632;&#x304E;&#x3001;

&#xBBF8;&#xD1A0; &#xCF58; &#xB4DC; &#xB9AC;&#xC544; &#xBA64;&#xBE0C;&#xB808;&#xC778; &#xC7A0;&#xC7AC;&#xC801; &#xC190;&#xC2E4; &#xC2EC;&#xAC01;&#xD55C; bioenergetic &#xACB0;&#xACFC; &#xC788;&#xC73C;&#xBA70; &#xC2EC;&#xADFC; &#xACBD;&#xC0C9;, &#xB1CC;&#xC878;&#xC911;, &#xC554;, neurodegeneration &#xB4F1; &#xB9CE;&#xC740; &#xC778;&#xAC04;&#xC758; &#xC9C8;&#xBCD1;&#xC5D0; &#xAE30;&#xC5EC; &#xD558; &#xACE0; &#xC788;&#xC2B5;&#xB2C8;&#xB2E4;. &#xADF8;&#xB7EC;&#xB098; &#xADF8; &#xB3CC;&#xAE30; &#xBC0F; &#xC138;&#xD3EC; &#xC5D0;&#xB108;&#xC9C0; &#xC0DD;&#xC0B0;&#xC758; &#xC911;&#xC694;&#xC131;&#xC5D0;&#xB3C4; &#xBD88;&#xAD6C; &#xD558; &#xACE0; &#xC7A0;&#xC7AC;&#xC801;&#xC778; &#xBBF8;&#xD1A0; &#xCF58; &#xB4DC; &#xB9AC;&#xC544; &#xBA64;&#xBE0C;&#xB808;&#xC778; &#xC124;&#xB9BD; &#xADF8;&#xAC83;&#xC5D0; &#xC758;&#xD558;&#xC5EC; &#xAE30;&#xBCF8;&#xC801;&#xC778; &#xBA54;&#xCEE4;&#xB2C8;&#xC998; &#xBD88;&#xBD84;&#xBA85; &#xB0A8;&#xC544; &#xC788;&#xC2B5;&#xB2C8;&#xB2E4;. &#xC6B0;&#xB9AC;&#xC758; &#xC5F0;&#xAD6C;&#xB294; &#xBCF5;&#xC7A1; &#xD55C; 2 &#xCC28; &#xAE30;&#xBC18; &#xC804;&#xC790; &#xD750;&#xB984; &#xAE30;&#xBCF8; &#xC758;&#xBBF8;&#xB294; &#xBBF8;&#xD1A0; &#xCF58; &#xB4DC; &#xB9AC;&#xC544; &#xBA64;&#xBE0C;&#xB808;&#xC778; hypoxic &#xC870;&#xAC74; &#xD558;&#xC5D0;&#xC11C; &#xD3B8;&#xAD11;&#xACFC; &#xD638;&#xBC15; &#xBCF4;&#xCDA9; &#xD558; &#xC5EC; &#xC2E0;&#xC18D; &#xD558; &#xAC8C; &#xBCF5;&#xC6D0;&#xD560; &#xC218; &#xC788;&#xB294; &#xC190;&#xC2E4;&#xC744; &#xAC00;&#xC5ED; &#xB9C9; &#xADC0;&#xCC29;&#xB418; &#xC5C8; &#xB2E4; &#xBCF5;&#xC7A1; &#xD55C; 2 &#xCC28; &#xAE30;&#xD310; &#xD638;&#xBC15;&#xC758; &#xADF8; &#xBD80;&#xC871;&#xC740; &#xBA85;&#xB8CC;. &#xBBF8;&#xD1A0; &#xCF58; &#xB4DC; &#xB9AC;&#xC544; &#xBCF5;&#xC7A1;&#xC758; &#xC800;&#xD574; &#xB098; &#xACE0; F (0) F (1)-ATP synthase &#xC720;&#xB3C4; &#xBBF8;&#xD1A0; &#xCF58; &#xB4DC; &#xB9AC;&#xC544; depolarization &#xBBF8;&#xD1A0; &#xCF58; &#xB4DC; &#xB9AC;&#xC544; &#xCE68;&#xD22C;&#xC131; &#xC804;&#xD658; &#xAE30; &#xACF5;, Bcl-2 (B-&#xC138;&#xD3EC; &#xB9BC;&#xD504; &#xC885; 2) &#xAC00;&#xC871; &#xB2E8;&#xBC31;&#xC9C8;, &#xB610;&#xB294; &#xB192;&#xC740; &#xC9C4;&#xD3ED; &#xBD93;&#xAE30;&#xC758; &#xB3C5;&#xB9BD; &#xB418;&#xC5C8;&#xACE0; &#xD638;&#xBC15;&#xC774; &#xB418;&#xB3CC;&#xB9B4; &#xC218; &#xC5C6;&#xC2B5;&#xB2C8;&#xB2E4;. &#xC911;&#xC694; &#xD55C; &#xAC83;&#xC740;, &#xD638;&#xBC15; &#xB300;&#xC0AC; hypoxic &#xC870;&#xAC74; &#xD558;&#xC5D0;&#xC11C; &#xB9C9; &#xC7A0;&#xC7AC;&#xB825;&#xACFC; ATP &#xC218;&#xC900; &#xBCF5;&#xC6D0;&#xD569;&#xB2C8;&#xB2E4;. &#xB610;&#xD55C;, &#xBCF5;&#xC7A1; &#xD55C; 2 &#xCC28; &#xC911;&#xC7AC; &#xC804;&#xC790; &#xD750;&#xB984;&#xC5D0; &#xB300; &#xD55C; &#xC2E0;&#xB8B0; &#xAE30;&#xB2A5; &#xBCF5;&#xC7A1; &#xD55C; &#xC5C6;&#xB294; &#xBBF8;&#xD1A0; &#xCF58; &#xB4DC; &#xB9AC;&#xC544; &#xC9C8;&#xD658; &#xD658;&#xC790;&#xC5D0;&#xC11C; &#xC140; &#xC218; &#xC788;&#xC2B5;&#xB2C8;&#xB2E4; &#xBBF8;&#xD1A0; &#xCF58; &#xB4DC; &#xB9AC;&#xC544; &#xBA64;&#xBE0C;&#xB808;&#xC778; &#xC7A0;&#xC7AC;&#xC801;&#xC778; &#xC804;&#xB2EC; &#xD558;&#xB294; &#xBBF8;&#xD1A0; &#xCF58; &#xB4DC;&#xB9AC; &#xC544; &#xAD6C;&#xC870;&#xC640; &#xCE7C;&#xC298; &#xAE38; &#xD56D; &#xC81C;&#xB97C; &#xC774;&#xC6A9;&#xD55C; &#xC815;&#xC0C1; &#xC138;&#xD3EC;&#xC640; &#xBE44;&#xC2B7;&#xD55C; &#xACA9;&#xB9AC; &#xD558;&#xB294; &#xAE30;&#xB2A5;&#xC744; &#xC720;&#xC9C0; &#xD558;&#xAE30; &#xC704;&#xD574; &#xB0B4;&#xAC00;. &#xC774; &#xBC1C;&#xACAC;&#xC740; &#xC911;&#xC694; hypoxia &#xC911; &#xBBF8;&#xD1A0; &#xCF58; &#xB4DC;&#xB9AC; &#xC544; &#xAE30;&#xB2A5;&#xC744; &#xC720;&#xC9C0; &#xD558;&#xAE30; &#xC704;&#xD574; &#xB9E4;&#xB825;&#xC801;&#xC778; &#xCE58;&#xB8CC;&#xB85C; &#xBCF5;&#xC7A1; &#xD55C; 2 &#xCC28; &#xAE30;&#xB2A5; &#xBCF4;&#xC874;&#xC744; &#xC704;&#xD55C; &#xBB34;&#xB300;&#xB97C; &#xC124;&#xC815; &#xD569;&#xB2C8;&#xB2E4;.

&#xBCF5;&#xC7A1; &#xD55C; 2 &#xCC28; &#xBBF8;&#xD1A0; &#xCF58; &#xB4DC; &#xB9AC;&#xC544; hypoxic &#xD558;&#xC9C0; &#xCE7C;&#xC298; &#xBC0F; proapoptotic Bcl-2 &#xB2E8;&#xBC31;&#xC9C8; &#xC720;&#xB3C4; &#xBBF8;&#xD1A0; &#xCF58; &#xB4DC; &#xB9AC;&#xC544; &#xBA64;&#xBE0C;&#xB808;&#xC778; &#xC7A0;&#xC7AC;&#xC801; &#xC190;&#xC2E4;&#xB9CC; &#xBC29;&#xC9C0;&#xD560; &#xC218; &#xC788;&#xC2B5;&#xB2C8;&#xB2E4;.

La p&#xE9;rdida de potencial de membrana mitocondrial tiene graves consecuencias bioenerg&#xE9;ticas y contribuye a muchas enfermedades humanas, incluyendo infarto de miocardio, accidente cerebrovascular, c&#xE1;ncer y la neurodegeneraci&#xF3;n. Sin embargo, a pesar de su protagonismo e importancia en la producci&#xF3;n de energ&#xED;a celular, el mecanismo b&#xE1;sico por el que se establece el potencial de membrana mitocondrial no est&#xE1; claro. Nuestros estudios de aclarar que el complejo II impulsado por el flujo de electrones es el principal medio por el cual la membrana mitocondrial se polariza en condiciones de hipoxia y que la falta de la succinato sustrato complejo II dio lugar a la p&#xE9;rdida de la membrana reversibles potencial que podr&#xED;a ser restaurado r&#xE1;pidamente por la suplementaci&#xF3;n con succinato. La inhibici&#xF3;n de complejo I mitocondrial y F (0) F (1)-ATP sintasa mitocondrial inducida por la despolarizaci&#xF3;n que era independiente del poro de transici&#xF3;n de permeabilidad mitocondrial, Bcl-2 (linfoma de c&#xE9;lulas B 2) prote&#xED;nas de la familia, o de gran amplitud hinchaz&#xF3;n y no pod&#xED;a ser invertida por succinato. Es importante destacar que el metabolismo del succinato en condiciones de hipoxia restaura los niveles de potencial de membrana y la ATP. Adem&#xE1;s, una dependencia de flujo de electrones complejo II mediada permite que las c&#xE9;lulas procedentes de pacientes con enfermedad mitocondrial desprovisto de un complejo funcional I para mantener un potencial de membrana mitocondrial que transmite tanto una estructura mitocondrial y la capacidad de secuestrar agonista inducida por calcio similar a la de las c&#xE9;lulas normales . Este hallazgo es importante ya que sienta las bases para la preservaci&#xF3;n complejo funcional II como un tratamiento atractivo para mantener la funci&#xF3;n mitocondrial durante la hipoxia.

Mitocondrial Complejo II Evita hip&#xF3;xico, pero no con calcio y pro-apopt&#xF3;ticos prote&#xED;na Bcl-2 inducida por la p&#xE9;rdida de potencial de membrana mitocondrial

We evaluated the presentation, treatment, and outcome of infants who present with ventricular tachycardia in the first year of life. Seventy-six infants were admitted to our institution with a diagnosis of ventricular tachycardia between January, 1987 and May, 2006. Forty-five infants were excluded from the study because of additional confounding diagnoses including accelerated idioventricular rhythm, Wolff-Parkinson-White syndrome, supraventricular tachycardia with aberrancy, long QT syndrome, cardiac rhabdomyoma, myocarditis, congenital lesions, or incomplete data. The remaining 31 included infants who had a median age at presentation of 1 day, with a range from 1 to 255 days, and a mean ventricular tachycardia rate of 213 beats per minute, with a range from 171 to 280, at presentation. The infants were treated chronically with propranolol (38.7%), amiodarone (12.9%), mexiletine (3.2%), propranolol and mexiletine (9.7%), or propranolol and procainamide (6.5%). The median duration of treatment was 13 months, with a range from 3 to 105 months. Ventricular tachycardia resolved spontaneously in all infants. No patient died, or received catheter ablation or device therapy. Median age at last ventricular tachycardia was 59 days, with a range from 1 to 836 days. Mean follow-up was 45 months, with a range from 5 to 164 months, with a mean ventricular tachycardia-free period of 40 months. Infants with asymptomatic ventricular tachycardia, a structurally normal heart, and no additional electrophysiological diagnosis all had spontaneous resolution of tachycardia. Furthermore, log-rank analysis of the time to ventricular tachycardia resolution showed no difference between children who received chronic outpatient anti-arrhythmic treatment and those who had no such therapy. While indications for therapy cannot be determined from this study, lack of symptoms or myocardial dysfunction suggests that therapy may not be necessary.

Ventricular tachycardia in infants with structurally normal heart: a benign disorder.

A mild method for the diastereoselective formation of C(4), C(5)-disubstituted cyclopentenones has been developed, involving formation of a pentadienyl cation via diastereoselective oxidation of a vinyl alkoxyallene. Conrotatory electrocyclization provides the cyclopentenone product. The broad scope, mild conditions, and uncommon substitution pattern accessible through this transformation make it a useful addition to the existing repertoire of cyclopentenone synthetic methods.

Oxidation-initiated Nazarov cyclization of vinyl alkoxyallenes.

Suppression of cyclooxygenase 2 (COX-2)-derived prostacyclin (PGI(2)) is sufficient to explain most elements of the cardiovascular hazard from nonsteroidal antinflammatory drugs (NSAIDs). However, randomized trials are consistent with the emergence of cardiovascular risk during chronic dosing with NSAIDs. Although deletion of the PGI(2) receptor fosters atherogenesis, the importance of COX-2 during development has constrained the use of conventional knockout (KO) mice to address this question. We developed mice in which COX-2 was deleted postnatally, bypassing cardiorenal defects exhibited by conventional KOs. When crossed into ApoE-deficient hyperlipidemic mice, COX-2 deletion accelerated atherogenesis in both genders, with lesions exhibiting leukocyte infiltration and phenotypic modulation of vascular smooth muscle cells, as reflected by loss of α-smooth muscle cell actin and up-regulation of vascular cell adhesion molecule-1. Stimulated peritoneal macrophages revealed suppression of COX-2-derived prostanoids and augmented 5-lipoxygenase product formation, consistent with COX-2 substrate rediversion. Although deletion of the 5-lipoxygenase activating protein (FLAP) did not influence atherogenesis, it attenuated the proatherogeneic impact of COX-2 deletion in hyperlipidemic mice. Chronic administration of NSAIDs may increasingly confer a cardiovascular hazard on patients at low initial risk. Promotion of atherogenesis by postnatal COX-2 deletion affords a mechanistic explanation for this observation. Coincident inhibition of FLAP may offer an approach to attenuating such a risk from NSAIDs.

Disruption of the 5-lipoxygenase pathway attenuates atherogenesis consequent to COX-2 deletion in mice.

An urgent need for new treatment modalities is emerging in elderly patients with acute myeloid leukemia (AML). We hypothesized that targeting VEGF might furnish an effective treatment modality in this population. Elderly patients with AML were randomly assigned in this phase 2 study (n = 171) to receive standard chemotherapy (3 + 7) with or without bevacizumab at a dose of 10 mg/kg intravenously at days 1 and 15. In the second cycle, patients received cytarabine 1000 mg/m(2) twice daily on days 1-6 with or without bevacizumab. The complete remission rates in the 2 arms were not different (65%). Event-free survival at 12 months was 33% for the standard arm versus 30% for the bevacizumab arm; at 24 months, it was 22% and 16%, respectively (P = .42). The frequencies of severe adverse events (SAEs) were higher in the bevacizumab arm (n = 63) compared with the control arm (n = 28; P = .043), but the percentages of death or life-threatening SAEs were lower in the bevacizumab arm (60% vs 75% of SAEs). The results of the present study show that the addition of bevacizumab to standard chemotherapy does not improve the therapeutic outcome of older AML patients. This trial is registered as number NTR904 in The Nederlands Trial Register (www.trialregister.nl).

Addition of bevacizumab to chemotherapy in acute myeloid leukemia at older age: a randomized phase 2 trial of the Dutch-Belgian Cooperative Trial Group for Hemato-Oncology (HOVON) and the Swiss Group for Clinical Cancer Research (SAKK).

A sp(3)-sp(2) C-C cross-coupling reaction catalyzed by gold in the absence of a sacrificial oxidant is described. Vital to the success of this method is the implementation of a bimetallic catalyst bearing a bis(phosphino)amine ligand. A mechanistic hypothesis is presented, and observable transmetalation, C-Br oxidative addition, and C-C reductive elimination in a model gold complex are shown. We expect that this method will serve as a platform for the development of novel transformations involving redox-active gold catalysts.

ArticleTotal : 2	Year
Publication title Cited by 4	2014
Publication title Cited by 10	2020

Article	Year
Changes in serum folate concentrations following voluntary food fortification in Australia. The Medical journal of Australia\| PubMed ID: 11936300	2002
N-cadherin haploinsufficiency affects cardiac gap junctions and arrhythmic susceptibility. Journal of molecular and cellular cardiology\| PubMed ID: 18201716	2008
Histone-deacetylase inhibition reverses atrial arrhythmia inducibility and fibrosis in cardiac hypertrophy independent of angiotensin. Journal of molecular and cellular cardiology\| PubMed ID: 18926829	2008
Cardiomyocyte cyclooxygenase-2 influences cardiac rhythm and function. Proceedings of the National Academy of Sciences of the United States of America\| PubMed ID: 19376970	2009
Melanocyte-like cells in the heart and pulmonary veins contribute to atrial arrhythmia triggers. The Journal of clinical investigation\| PubMed ID: 19855129	2009
Mitochondrial complex II prevents hypoxic but not calcium- and proapoptotic Bcl-2 protein-induced mitochondrial membrane potential loss. The Journal of biological chemistry\| PubMed ID: 20566649	2010
Ventricular tachycardia in infants with structurally normal heart: a benign disorder. Cardiology in the young\| PubMed ID: 20723269	2010
Oxidation-initiated Nazarov cyclization of vinyl alkoxyallenes. Organic letters\| PubMed ID: 21155592	2011
Disruption of the 5-lipoxygenase pathway attenuates atherogenesis consequent to COX-2 deletion in mice. Proceedings of the National Academy of Sciences of the United States of America\| PubMed ID: 22493243	2012
Addition of bevacizumab to chemotherapy in acute myeloid leukemia at older age: a randomized phase 2 trial of the Dutch-Belgian Cooperative Trial Group for Hemato-Oncology (HOVON) and the Sw... Blood\| PubMed ID: 23047822	2012
Gold-catalyzed allylation of aryl boronic acids: accessing cross-coupling reactivity with gold. Angewandte Chemie (International ed. in English)\| PubMed ID: 24799132	2014

Mark D. Levin

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