murine-left-anterior-descending-lad-coronary-artery-ligation-an

Murine Left Anterior Descending (LAD) Coronary Artery Ligation: An Improved and Simplified Model for Myocardial Infarction

Ischemic heart disease (IHD), or acute coronary syndrome (ACS), is one of the leading causes of death in the United States. IHD is characterized by ...

Rhode Island Hospital, Brown University Warren Alpert Medical School

Cisplatin (cis-diamminedichloroplatinum(II)) is an effective chemotherapeutic agent, and is successfully used in the treatment of a wide range of tumors. Despite its effectiveness as an anti-tumor drug, nephrotoxic side effects have significantly restricted its clinical use. Tubular epithelial cell deletion following cisplatin treatment is a major cause of renal injury. Oxidative stress significantly contributes to cisplatin-associated cytotoxicity, and use of antioxidants could counteract such cytotoxic effects of cisplatin. The renal microenvironmental changes following cisplatin treatment is a complex process and could be broadly categorized into three main pathological events, which at times might overlap: initial cytotoxic events, inflammatory events and fibroproliferative events. Stress responses and heat shock proteins generated following cisplatin treatment are actively involved in the initiation and progression of these events. In this article, we will briefly summarize factors involved in various phases of cisplatin-induced renal injuries.

Cisplatin-associated nephrotoxicity and pathological events.

Despite recent progress in identifying a number of important factors that may play central roles in various renal diseases, the precise molecular basis of renal injuries remains unclear. Recent studies have documented an important role for oxidant stress in several renal diseases. Oxidant stress by overproduction of reactive oxygen species, generation of reactive nitrogen species, and/or modulation of cellular antioxidant enzyme activities, resulting in the activation of certain transcription factors, and synthesis and/or release of inflammatory cytokines, chemokines, growth factors, and extracellular matrix proteins. These changes alter the balance in the microenvironment of the kidney, and may activate signaling cascades that induce and propagate renal injury. Complex molecular interactions and cross-talk between the activated signaling pathways, in turn, define the nature and clinical course of the disease process. In this article, we will briefly present the relevance of the oxidant stress in the pathogenesis of various renal diseases.

Oxidant stress in renal pathophysiology.

&#x53D7;&#x4F53;&#x4ECB;&#x5BFC;&#x7684;&#x4FE1;&#x53F7;&#x8F6C;&#x5BFC;&#x662F;&#x5E38;&#x4E0E;&#x591A;&#x4E2A;&#x51FD;&#x6570;&#xFF0C;&#x5305;&#x62EC;&#x751F;&#x4EA7;&#x7684;&#x6D3B;&#x6027;&#x6C27;&#x7269;&#x79CD;&#x76F8;&#x5173;&#x8054;&#x3002;&#x4F46;&#x662F;&#xFF0C;&#x662F;&#x5426;&#x6E90;&#x6027;&#x7EBF;&#x7C92;&#x4F53;&#x8D85;&#x6C27; (&#x6D17;) &#x76F4;&#x63A5;&#x6709;&#x52A9;&#x4E8E;&#x751F;&#x7406;&#x4FE1;&#x53F7;&#x662F;&#x6709;&#x4E89;&#x8BAE;&#x7684;&#x3002;&#x5728;&#x8FD9;&#x91CC;&#x6211;&#x4EEC;&#x5C55;&#x793A;&#x7684;&#x751F;&#x7406; Ca(2+) &#x8BF1;&#x53D1;&#x6D17;&#x751F;&#x4EA7;&#x53D1;&#x6325;&#x4E86;&#x5173;&#x952E;&#x4F5C;&#x7528;&#x5185;, &#x76AE;&#x7EC6;&#x80DE; (EC) &#x6FC0;&#x6D3B;&#x548C;&#x767D;&#x7EC6;&#x80DE;&#x575A;&#x5B9A;&#x9ECF;&#x9644;&#x5728;&#x4EE5;&#x524D;&#x672A;&#x77E5;&#x7684;&#x673A;&#x5236;&#x3002;G &#x86CB;&#x767D;&#x5076;&#x8054;&#x53D7;&#x4F53; (&#x6C14;&#x76F8;) &#x548C;&#x916A;&#x6C28;&#x9178;&#x6FC0;&#x9176;&#x4ECB;&#x5BFC;&#x808C;&#x9187; 1,4,5 &#x5185;&#x4F9D;&#x8D56;&#x7EBF;&#x7C92;&#x4F53;&#x7ECF;&#x5438;&#x6536;&#x5BFC;&#x81F4; NADPH &#x6C27;&#x5316;&#x9176;&#x72EC;&#x7ACB;&#x6D17;&#x751F;&#x4EA7;&#x3002;&#x4F46;&#x662F;&#xFF0C;&#x6C14;&#x76F8;&#x5316;&#x5B66;&#x8FD8;&#x539F;&#x94FE;&#x63A5;&#x6D17;&#x751F;&#x4EA7;&#x5E76;&#x6CA1;&#x6709;&#x6539;&#x53D8;&#x7EBF;&#x7C92;&#x4F53;&#x7684;&#x51FD;&#x6570;&#x6216;&#x89E6;&#x53D1;&#x5668;&#x7EC6;&#x80DE;&#x6B7B;&#x4EA1;&#xFF0C;&#x800C;&#x662F;&#x6709;&#x52A9;&#x4E8E;&#x6FC0;&#x6D3B;&#x901A;&#x8FC7;&#x6B27;&#x5171;&#x4F53;&#x8BF1;&#x5BFC;&#x7EC6;&#x80DE;&#x95F4;&#x7C98;&#x9644;&#x5206;&#x5B50; 1 NF &#x6D3B;&#x5316;&#x548C;&#x767D;&#x7EC6;&#x80DE;&#x7C98;&#x9644;&#x3002;&#x9530;&#x8D85;&#x6C27;&#x5316;&#x7269;&#x6B67;&#x5316;&#x9176;&#x8868;&#x8FBE;&#x548C;&#x6A21;&#x62DF;&#x5355;&#x5143; permeative &#x7684;&#x8D85;&#x6C27;&#x5316;&#x7269;&#x6B67;&#x5316;&#x9176;&#x6D17;&#x6B67;&#x5316;&#x70E7;&#x8680; NF &#x6D3B;&#x5316;&#x8F6C;&#x5F55;&#x6D3B;&#x6027;&#x548C;&#x4FC3;&#x8FDB;&#x4E0B;&#x6A21;&#x62DF;&#x5FAA;&#x73AF;&#x540E;&#x6C14;&#x76F8;&#x5316;&#x5B66;&#x8FD8;&#x539F;-&#x4F46;&#x4E0D;&#x662F;&#x7EC6;&#x80DE;&#x56E0;&#x5B50;&#x8BF1;&#x5BFC;&#x6FC0;&#x6D3B;&#x5185;&#x76AE;&#x7EC6;&#x80DE;&#x767D;&#x7EC6;&#x80DE;&#x8131;&#x79BB;&#x3002;&#x8FD9;&#x4E9B;&#x7ED3;&#x679C;&#x8868;&#x660E;&#xFF0C;&#x6D17;&#x662F;&#x53D7;&#x4F53;&#x4ECB;&#x5BFC;&#x7ECF;&#x4FE1;&#x53F7;&#x8F6C;&#x5316;&#x4E3A;&#x708E;&#x6027;&#x4FE1;&#x53F7;&#x548C;&#x767D;&#x7EC6;&#x80DE;/EC &#x575A;&#x5B9A;&#x7C98;&#x9644;&#x7684;&#x4E0B;&#x6E38;&#x6548;&#x5E94;&#x5206;&#x5B50;&#x3002;

G &#x86CB;&#x767D;&#x5076;&#x8054;&#x53D7;&#x4F53; Ca2 +-&#x94FE;&#x63A5;&#x7EBF;&#x7C92;&#x4F53;&#x7684;&#x6D3B;&#x6027;&#x6C27;&#x7269;&#x79CD;&#x7684;&#x5185;&#x76AE;&#x7EC6;&#x80DE;&#x767D;&#x7EC6;&#x80DE;/&#x9075;&#x5B88;&#x81F3;&#x5173;&#x91CD;&#x8981;&#x3002;

Receptor-mediated signaling is commonly associated with multiple functions, including the production of reactive oxygen species. However, whether mitochondrion-derived superoxide (mROS) contributes directly to physiological signaling is controversial. Here we demonstrate a previously unknown mechanism in which physiologic Ca(2+)-evoked mROS production plays a pivotal role in endothelial cell (EC) activation and leukocyte firm adhesion. G protein-coupled receptor (GPCR) and tyrosine kinase-mediated inositol 1,4,5-trisphosphate-dependent mitochondrial Ca(2+) uptake resulted in NADPH oxidase-independent mROS production. However, GPCR-linked mROS production did not alter mitochondrial function or trigger cell death but rather contributed to activation of NF-kappaB and leukocyte adhesion via the EC induction of intercellular adhesion molecule 1. Dismutation of mROS by manganese superoxide dismutase overexpression and a cell-permeative superoxide dismutase mimetic ablated NF-kappaB transcriptional activity and facilitated leukocyte detachment from the endothelium under simulated circulation following GPCR- but not cytokine-induced activation. These results demonstrate that mROS is the downstream effector molecule that translates receptor-mediated Ca(2+) signals into proinflammatory signaling and leukocyte/EC firm adhesion.

G protein-coupled receptor Ca2+-linked mitochondrial reactive oxygen species are essential for endothelial/leukocyte adherence.

M&#xE9;di&#xE9;e par le r&#xE9;cepteur de signalisation est souvent associ&#xE9;e &#xE0; de multiples fonctions, y compris la production d&#x26;#39;esp&#xE8;ces r&#xE9;actives de l&#x26;#39;oxyg&#xE8;ne. Toutefois, si mitochondrie d&#xE9;riv&#xE9; dismutase (MROS) contribue directement &#xE0; la signalisation physiologique est controvers&#xE9;e. Ici, nous d&#xE9;montrons un m&#xE9;canisme jusqu&#x26;#39;alors inconnu dans lequel physiologique Ca (2 +)-a &#xE9;voqu&#xE9; la production MROS joue un r&#xF4;le central dans la cellule (CE) activation endoth&#xE9;liale et l&#x26;#39;adh&#xE9;rence des leucocytes cabinet. G r&#xE9;cepteur coupl&#xE9; aux prot&#xE9;ines (RCPG) et la tyrosine kinase m&#xE9;di&#xE9;e par l&#x26;#39;inositol 1,4,5-triphosphate-d&#xE9;pendant mitochondrial Ca (2 +) conduit &#xE0; l&#x26;#39;absorption NADPH oxydase-production ind&#xE9;pendante MROS. Cependant, RCPG-li&#xE9;e de production MROS ne modifie pas la fonction mitochondriale ou la mort cellulaire de d&#xE9;clenchement mais contribu&#xE9; &#xE0; l&#x26;#39;activation de NF-kB et l&#x26;#39;adh&#xE9;rence des leucocytes par l&#x26;#39;interm&#xE9;diaire du induction CE d&#x26;#39;une mol&#xE9;cule d&#x26;#39;adh&#xE9;sion intercellulaire. Dismutation du MROS par la surexpression de mangan&#xE8;se superoxyde dismutase et une cellule-permeative superoxyde dismutase mim&#xE9;tique ablation NF-kappaB activit&#xE9; transcriptionnelle et facilit&#xE9; de d&#xE9;tachement des leucocytes de l&#x26;#39;endoth&#xE9;lium dans la circulation simul&#xE9;e suite &#xE0; l&#x26;#39;activation de GPCR, mais pas induite par les cytokines. Ces r&#xE9;sultats d&#xE9;montrent que le MROS est la mol&#xE9;cule effecteur en aval qui se traduit m&#xE9;di&#xE9;s par les r&#xE9;cepteurs Ca (2 +) en signaux de signalisation pro-inflammatoire et l&#x26;#39;adh&#xE9;rence des leucocytes cabinet / CE.

G r&#xE9;cepteur coupl&#xE9; aux prot&#xE9;ines Ca2 + li&#xE9; mitochondriales esp&#xE8;ces r&#xE9;actives de l&#x26;#39;oxyg&#xE8;ne sont essentielles pour endoth&#xE9;liale / leucocytes adh&#xE9;sion

Rezeptor-vermittelte Signalisierung ist allgemein im Zusammenhang mit mehreren Funktionen, einschlie&szlig;lich der Produktion von reaktiven Sauerstoffspezies. Ob Mitochondrium abgeleitete Superoxid (mROS) direkt zur physiologischen Signalisierung beitr&auml;gt ist jedoch umstritten. Hier zeigen wir einen bisher unbekannten Mechanismus, in dem physiologischen Ca(2+) evoziert mROS Produktion in Endothelzellen (EG) Aktivierung und Leukozyten feste Adh&auml;sion eine entscheidende Rolle spielt. G-Protein-gekoppelter Rezeptor (GPCR) und Tyrosin Kinase-vermittelte Inosit 1,4,5-Trisphosphate-abh&auml;ngige mitochondriale Ca(2+) Aufnahme f&uuml;hrte NADPH Oxydase-unabh&auml;ngige mROS Produktion. GPCR-chromosomale mROS Produktion mitochondriale Funktion oder eines Triggers Zelltod nicht ver&auml;ndern jedoch eher zur Aktivierung von NF-KappaB und Leukozyten Adh&auml;sion &uuml;ber die EG-Induktion von der Adh&auml;sion Molek&uuml;l 1 beigetragen. Dismutation von mROS von Mangan-Superoxid-Dismutase-&Uuml;berexpression und eine Zelle-permeative Superoxid-Dismutase mimetischen ablated NF-KappaB transkriptionelle Aktivit&auml;t und erleichtert Leukozyten Anhaftung an das Endothel unter simulierten Zirkulation nach GPCR - aber nicht Zytokin-induzierte Aktivierung. Diese Ergebnisse zeigen, dass mROS das nachgeschaltete Effektor-Molek&uuml;l ist, das Rezeptor-vermittelte Ca(2+) Signale in Proinflammatory Signalisierung und Leukozyten/EG feste Adh&auml;sion &uuml;bersetzt.

G-Protein-gekoppelter Rezeptor Ca2 +-verkn&uuml;pfte mitochondriale reaktive Sauerstoffspezies sind unerl&auml;sslich f&uuml;r die Einhaltung der endothelial/Leukozyten.

Recettore-mediata segnalazione &egrave; comunemente associato con molteplici funzioni, tra cui la produzione di specie reattive dell&#39;ossigeno. Tuttavia, se derivato da mitocondrio superossido (mROS) contribuisce direttamente alla segnalazione fisiologica &egrave; controversa. Qui mostriamo un meccanismo precedentemente sconosciuto in cui fisiologica produzione mROS evocato Ca(2+) gioca un ruolo cardine nella cellula endoteliale (CE) attivazione e leucocita ferma aderenza. Recettori accoppiati a proteine G (GPCR) e assorbimento di tirosina chinasi mediata inositolo 1.4.5-trifosfato-dipendente mitocondriale Ca(2+) portato nella produzione di NADPH ossidasi-indipendente mROS. Tuttavia, produzione legata al GPCR mROS non alterava mitocondriale funzione o un trigger di morte delle cellule ma piuttosto contribuito all&#39;attivazione di NF-kappaB e leucocita adesione tramite l&#39;induzione di CE della molecola di adesione intercellulare 1. Dismutazione di mROS dalla sovraespressione di manganese superossido dismutasi e una cella-neutralizzare superossido dismutasi mimetico ablazione attivit&agrave; trascrizionale NF-kappaB e facilitato il distacco dei leucociti da endotelio sotto circolazione simulato seguito GPCR - ma non indotta da citochine attivazione. Questi risultati dimostrano che mROS &egrave; la molecola effector downstream che traduce mediata dal recettore Ca(2+) segnali proinfiammatori segnalazione e leucociti/CE ferma adesione.

Dei recettori accoppiati a proteine G Ca2 +-specie ossigenate reattive mitocondriali collegati sono essenziali per l&#39;adesione endoteliale/leucocitarie.

&#x53D7;&#x5BB9;&#x4F53;&#x3092;&#x4ECB;&#x3059;&#x308B;&#x30B7;&#x30B0;&#x30CA;&#x30EB;&#x4F1D;&#x9054;&#x306F;&#x3001;&#x4E00;&#x822C;&#x306B;&#x6D3B;&#x6027;&#x9178;&#x7D20;&#x7A2E;&#x306E;&#x7523;&#x751F;&#x3092;&#x542B;&#x3080;&#x8907;&#x6570;&#x306E;&#x6A5F;&#x80FD;&#x306B;&#x95A2;&#x9023;&#x4ED8;&#x3051;&#x3089;&#x308C;&#x3066;&#x3044;&#x307E;&#x3059;&#x3002;&#x3057;&#x304B;&#x3057;&#x3001;&#x30DF;&#x30C8;&#x30B3;&#x30F3;&#x30C9;&#x30EA;&#x30A2;&#x7531;&#x6765;&#x306E;&#x30B9;&#x30FC;&#x30D1;&#x30FC;&#x30AA;&#x30AD;&#x30B7;&#x30C9;&#x304B;&#x3069;&#x3046;&#x304B;&#xFF08;mROS&#xFF09;&#x7269;&#x8B70;&#x3092;&#x91B8;&#x3057;&#x3066;&#x3044;&#x308B;&#x751F;&#x7406;&#x7684;&#x306A;&#x30B7;&#x30B0;&#x30CA;&#x30EB;&#x4F1D;&#x9054;&#x306B;&#x76F4;&#x63A5;&#x8CA2;&#x732E;&#x3057;&#x3066;&#x3044;&#x307E;&#x3059;&#x3002;&#x3053;&#x3053;&#x3067;&#x306F;&#x3001;&#x751F;&#x7406;&#x7684;&#x306A;Ca&#xFF08;2 +&#xFF09;&#x306E;&#x8A98;&#x767A;mROS&#x306E;&#x751F;&#x7523;&#x306F;&#x5185;&#x76AE;&#x7D30;&#x80DE;&#xFF08;EC&#xFF09;&#x306E;&#x6D3B;&#x6027;&#x5316;&#x3068;&#x767D;&#x8840;&#x7403;&#x5F37;&#x56FA;&#x306A;&#x63A5;&#x7740;&#x306B;&#x91CD;&#x8981;&#x306A;&#x5F79;&#x5272;&#x3092;&#x679C;&#x305F;&#x3057;&#x3066;&#x3044;&#x308B;&#x672A;&#x77E5;&#x306E;&#x30E1;&#x30AB;&#x30CB;&#x30BA;&#x30E0;&#x3092;&#x793A;&#x3057;&#x3066;&#x3044;&#x307E;&#x3059;&#x3002; G&#x30BF;&#x30F3;&#x30D1;&#x30AF;&#x8CEA;&#x5171;&#x5F79;&#x578B;&#x53D7;&#x5BB9;&#x4F53;&#xFF08;GPCR&#xFF09;&#x3068;&#x30C1;&#x30ED;&#x30B7;&#x30F3;&#x30AD;&#x30CA;&#x30FC;&#x30BC;&#x3092;&#x4ECB;&#x3057;&#x305F;&#x30A4;&#x30CE;&#x30B7;&#x30C8;&#x30FC;&#x30EB;1,4,5  - &#x4E09;&#x30EA;&#x30F3;&#x9178;&#x4F9D;&#x5B58;&#x6027;&#x306E;&#x30DF;&#x30C8;&#x30B3;&#x30F3;&#x30C9;&#x30EA;&#x30A2;&#x306E;Ca&#xFF08;2 +&#xFF09;&#x306E;&#x53D6;&#x308A;&#x8FBC;&#x307F;&#x306F;&#x3001;NADPH&#x30AA;&#x30AD;&#x30B7;&#x30C0;&#x30FC;&#x30BC;&#x4F9D;&#x5B58;&#x3057;&#x306A;&#x3044;mROS&#x306E;&#x751F;&#x7523;&#x3092;&#x3082;&#x305F;&#x3089;&#x3057;&#x305F;&#x3002;&#x3057;&#x304B;&#x3057;&#x3001;GPCR&#x306B;&#x30EA;&#x30F3;&#x30AF;&#x3055;&#x308C;&#x305F;mROS&#x751F;&#x7523;&#x306F;&#x30DF;&#x30C8;&#x30B3;&#x30F3;&#x30C9;&#x30EA;&#x30A2;&#x6A5F;&#x80FD;&#x3084;&#x30C8;&#x30EA;&#x30AC;&#x306E;&#x7D30;&#x80DE;&#x6B7B;&#x3092;&#x5909;&#x66F4;&#x3059;&#x308B;&#x3053;&#x3068;&#x306F;&#x306A;&#x304F;&#x3001;NF-&#x3BA;B&#x306E;&#x6D3B;&#x6027;&#x5316;&#x200B;&#x200B;&#x3068;&#x7D30;&#x80DE;&#x9593;&#x63A5;&#x7740;&#x5206;&#x5B50;1&#x306E;EC&#x306E;&#x8A98;&#x5C0E;&#x3092;&#x4ECB;&#x3057;&#x3066;&#x767D;&#x8840;&#x7403;&#x306E;&#x63A5;&#x7740;&#x306B;&#x5BC4;&#x4E0E;&#x3057;&#x3066;&#x3044;&#x307E;&#x305B;&#x3093;&#x3067;&#x3057;&#x305F;&#x3002; GPCR  - &#x3057;&#x304B;&#x3057;&#x3001;&#x30B5;&#x30A4;&#x30C8;&#x30AB;&#x30A4;&#x30F3;&#x8A98;&#x5C0E;&#x3057;&#x306A;&#x3044;&#x30A2;&#x30AF;&#x30C6;&#x30A3;&#x30D9;&#x30FC;&#x30B7;&#x30E7;&#x30F3;&#x5F8C;&#x306B;&#x30DE;&#x30F3;&#x30AC;&#x30F3;&#x30B9;&#x30FC;&#x30D1;&#x30FC;&#x30AA;&#x30AD;&#x30B7;&#x30C9;&#x30B8;&#x30B9;&#x30E0;&#x30BF;&#x30FC;&#x30BC;&#x306E;&#x904E;&#x5270;&#x767A;&#x73FE;&#x3068;&#x7D30;&#x80DE;permeative&#x30B9;&#x30FC;&#x30D1;&#x30FC;&#x30AA;&#x30AD;&#x30B7;&#x30C9;&#x30B8;&#x30B9;&#x30E0;&#x30BF;&#x30FC;&#x30BC;&#x6A21;&#x5023;&#x30A2;&#x30D6;&#x30EC;&#x30FC;&#x30B7;&#x30E7;&#x30F3;NF-&#x3BA;B&#x306E;&#x8EE2;&#x5199;&#x6D3B;&#x6027;&#x3068;&#x30B7;&#x30DF;&#x30E5;&#x30EC;&#x30FC;&#x30C8;&#x3055;&#x308C;&#x305F;&#x5FAA;&#x74B0;&#x4E0B;&#x306E;&#x5185;&#x76AE;&#x7D30;&#x80DE;&#x304B;&#x3089;&#x5BB9;&#x6613;&#x306B;&#x767D;&#x8840;&#x7403;&#x5206;&#x96E2;&#x306B;&#x3088;&#x3063;&#x3066;mROS&#x306E;&#x4E0D;&#x5747;&#x5316;&#x3002;&#x3053;&#x308C;&#x3089;&#x306E;&#x7D50;&#x679C;&#x306F;mROS&#x306F;&#x3001;&#x708E;&#x75C7;&#x6027;&#x30B7;&#x30B0;&#x30CA;&#x30EA;&#x30F3;&#x30B0;&#x304A;&#x3088;&#x3073;&#x767D;&#x8840;&#x7403;/ EC&#x5F37;&#x56FA;&#x306A;&#x63A5;&#x7740;&#x306B;&#x53D7;&#x5BB9;&#x4F53;&#x3092;&#x4ECB;&#x3057;&#x305F;Ca&#xFF08;2 +&#xFF09;&#x306E;&#x4FE1;&#x53F7;&#x3092;&#x5909;&#x63DB;&#x3059;&#x308B;&#x4E0B;&#x6D41;&#x306E;&#x30A8;&#x30D5;&#x30A7;&#x30AF;&#x30BF;&#x30FC;&#x5206;&#x5B50;&#x3067;&#x3042;&#x308B;&#x3053;&#x3068;&#x3092;&#x793A;&#x3057;&#x3066;&#x3044;&#x308B;&#x3002;

+&#x30EA;&#x30F3;&#x30AF;&#x3055;&#x308C;&#x305F;&#x30DF;&#x30C8;&#x30B3;&#x30F3;&#x30C9;&#x30EA;&#x30A2;&#x6D3B;&#x6027;&#x9178;&#x7D20;&#x7A2E;&#x304C;&#x5185;&#x76AE;/&#x767D;&#x8840;&#x7403;&#x4ED8;&#x7740;&#x306B;&#x5FC5;&#x9808;&#x3067;&#x3042;&#x308B;G&#x30BF;&#x30F3;&#x30D1;&#x30AF;&#x8CEA;&#x5171;&#x5F79;&#x578B;&#x53D7;&#x5BB9;&#x4F53;&#x30AB;&#x30EB;&#x30B7;&#x30A6;&#x30E0;

&#xC2E0;&#xD638; &#xC218;&#xC6A9; &#xCCB4;-&#xC911;&#xC7AC; &#xBC18;&#xC751; &#xC0B0;&#xC18C; &#xC885;&#xC758; &#xC0DD;&#xC0B0;&#xC744; &#xD3EC;&#xD568; &#xD55C; &#xC5EC;&#xB7EC; &#xAE30;&#xB2A5;&#xC5D0; &#xC77C;&#xBC18;&#xC801;&#xC73C;&#xB85C; &#xC5F0;&#xACB0; &#xB429;&#xB2C8;&#xB2E4;. &#xADF8;&#xB7EC;&#xB098; mitochondrion &#xD30C;&#xC0DD; superoxide (mROS) &#xC0DD;&#xB9AC; &#xC2E0;&#xD638;&#xC5D0; &#xC9C1;&#xC811; &#xAE30;&#xC5EC; &#xD558;&#xB294; &#xC5EC;&#xBD80;&#xB294; &#xB17C;&#xB780;&#xC785;&#xB2C8;&#xB2E4;. &#xC5EC;&#xAE30; physiologic Ca(2+) &#xAC16;&#xB294; mROS &#xC0DD;&#xC0B0; &#xB0B4; &#xD53C; &#xC138;&#xD3EC; (EC) &#xD65C;&#xC131;&#xD654; &#xBC0F; &#xBC31;&#xD608;&#xAD6C; &#xD68C;&#xC0AC; &#xC811;&#xCC29;&#xC5D0; &#xC911;&#xCD94;&#xC801;&#xC778; &#xC5ED;&#xD560;&#xC744; &#xD55C;&#xB2E4; &#xC774;&#xC804;&#xC5D0; &#xC54C; &#xC218; &#xC5C6;&#xB294; &#xBA54;&#xCEE4;&#xB2C8;&#xC998;&#xC744; &#xBCF4;&#xC5EC; &#xC90D;&#xB2C8;&#xB2E4;. G &#xB2E8;&#xBC31;&#xC9C8; &#xACB0;&#xD569; &#xC218;&#xC6A9; &#xCCB4; (GPCR)&#xACFC; &#xD2F0;&#xB85C;&#xC2E0; &#xD0A4; &#xB2C8; &#xC544; &#xC81C; &#xC911;&#xC7AC; inositol 1,4,5 trisphosphate &#xC885;&#xC18D; &#xBBF8;&#xD1A0; &#xCF58; &#xB4DC;&#xB9AC; &#xC544; Ca(2+) &#xAE00;&#xADC0; NADPH &#xC0B0;&#xD654; &#xD6A8;&#xC18C; &#xB3C5;&#xB9BD;&#xC801;&#xC778; mROS &#xC0DD;&#xC0B0; &#xADC0;&#xCC29;&#xB418; &#xC5C8; &#xB2E4;. &#xADF8;&#xB7EC;&#xB098;, GPCR&#xC5D0; &#xC5F0;&#xACB0; &#xB41C; mROS &#xC0DD;&#xC0B0; &#xBBF8;&#xD1A0; &#xCF58; &#xB4DC; &#xB9AC;&#xC544; &#xAE30;&#xB2A5; &#xB610;&#xB294; &#xD2B8;&#xB9AC;&#xAC70; &#xC138;&#xD3EC; &#xC8FD;&#xC74C;&#xC744; &#xBCC0;&#xACBD; &#xD558;&#xC9C0; &#xC54A;&#xC558;&#xB2E4; &#xD558;&#xC9C0;&#xB9CC; &#xC624;&#xD788;&#xB824; &#xC138;&#xD3EC; &#xC811;&#xCC29; &#xBD84;&#xC790; 1 EC &#xC720;&#xB3C4; &#xD1B5;&#xD574; NF kappaB &#xBC0F; &#xBC31;&#xD608;&#xAD6C; &#xC811;&#xCC29;&#xC758; &#xD65C;&#xC131;&#xD654;&#xC5D0; &#xAE30;&#xC5EC;. &#xB9DD;&#xAC04; superoxide dismutase overexpression &#xBC0F; permeative &#xC140; superoxide dismutase &#xBAA8;&#xBC29; &#xD558; &#xC5EC; Mros&#xC758; dismutation ablated NF kappaB transcriptional &#xD65C;&#xB3D9; &#xBC0F; &#xB2E4;&#xC74C;&#xACFC; &#xAC19;&#xC740; GPCR-&#xD65C;&#xC131;&#xD654; &#xD558;&#xC9C0; cytokine &#xC720;&#xB3C4; &#xD558;&#xC9C0;&#xB9CC; &#xC2DC;&#xBBAC;&#xB808;&#xC774;&#xC158;&#xB41C; &#xC21C;&#xD658;&#xC5D0;&#xC11C; endothelium&#xC5D0;&#xC11C; &#xBC31;&#xD608;&#xAD6C; &#xBD84;&#xB9AC;&#xB97C; &#xCD09;&#xC9C4;. &#xC774;&#xB7EC;&#xD55C; &#xACB0;&#xACFC; mROS proinflammatory &#xC2E0;&#xD638; &#xBC0F; &#xBC31;&#xD608;&#xAD6C;/EC &#xD68C;&#xC0AC; &#xC811;&#xCC29;&#xC73C;&#xB85C; &#xC218;&#xC6A9; &#xCCB4;-&#xC911;&#xC7AC; Ca(2+) &#xC2E0;&#xD638;&#xB97C; &#xBCC0;&#xD658; &#xD558;&#xB294; &#xB2E4;&#xC6B4;&#xC2A4;&#xD2B8;&#xB9BC; &#xC774;&#xD399;&#xD130; &#xBD84;&#xC790; &#xC774;&#xB2E4; &#xD558;&#xB294; &#xBC29;&#xBC95;&#xC744; &#xBCF4;&#xC5EC; &#xC90D;&#xB2C8;&#xB2E4;.

G &#xB2E8;&#xBC31;&#xC9C8; &#xACB0;&#xD569; &#xC218;&#xC6A9; &#xCCB4; Ca2 +-&#xC5F0;&#xACB0; &#xB41C; &#xBBF8;&#xD1A0; &#xCF58; &#xB4DC;&#xB9AC; &#xC544; &#xBC18;&#xC751; &#xC0B0;&#xC18C; &#xC885;&#xC758; &#xB0B4; &#xD53C;/&#xBC31;&#xD608;&#xAD6C; &#xC900;&#xC218;&#xC5D0; &#xB300; &#xD55C; &#xD544;&#xC218;&#xC801;&#xC785;&#xB2C8;&#xB2E4;.

Mediada por los receptores de se&#xF1;alizaci&#xF3;n se asocia con m&#xFA;ltiples funciones, incluyendo la producci&#xF3;n de especies reactivas del ox&#xED;geno. Sin embargo, si la mitocondria derivado de super&#xF3;xido (OPF), contribuye directamente a la se&#xF1;alizaci&#xF3;n fisiol&#xF3;gica es controvertida. Aqu&#xED; se demuestra un mecanismo previamente desconocido en el que fisiol&#xF3;gica de Ca (2 +)-evoc&#xF3; la producci&#xF3;n OPF juega un papel fundamental en las c&#xE9;lulas endoteliales (CE) la activaci&#xF3;n y la firme adhesi&#xF3;n de leucocitos. La prote&#xED;na G-receptor acoplado (GPCR) y la tirosina quinasa mediada por inositol 1,4,5-trifosfato mitocondrial dependiente de Ca (2 +) dio lugar a la absorci&#xF3;n de la NADPH oxidasa independiente de la producci&#xF3;n de OPF. Sin embargo, la producci&#xF3;n vinculada a GPCR OPF no alterar la funci&#xF3;n mitocondrial o activan la muerte celular, sino que contribuy&#xF3; a la activaci&#xF3;n de NF-kappaB y la adhesi&#xF3;n de leucocitos a trav&#xE9;s de la inducci&#xF3;n de la CE, mol&#xE9;cula de adhesi&#xF3;n intercelular 1. Dismutaci&#xF3;n del OPF por la sobreexpresi&#xF3;n de manganeso super&#xF3;xido dismutasa y un tel&#xE9;fono permeativo mim&#xE9;tica super&#xF3;xido dismutasa ablaci&#xF3;n de NF-kappaB y el desprendimiento de la actividad transcripcional facilita leucocitos del endotelio en la circulaci&#xF3;n despu&#xE9;s de la activaci&#xF3;n simulada GPCR, pero no inducida por las citoquinas. Estos resultados demuestran que las OPF es la mol&#xE9;cula de efector que traduce mediados por receptores de Ca (2 +) en las se&#xF1;ales de se&#xF1;alizaci&#xF3;n proinflamatoria y leucocitos / CE adhesi&#xF3;n firme.

G receptor acoplado a prote&#xED;na Ca2 + mitocondrial ligada a especies reactivas del ox&#xED;geno son esenciales para endotelial / leucocitos Adherencia

Calpain is a family of cysteine proteases that has an important role in the initiation, regulation, and execution of cell death. Our recent studies using a hypercholesterolemic swine model demonstrated that in the setting of the metabolic syndrome, calpain inhibition (CI) improved collateral-dependent perfusion and increased expression of proteins implicated in angiogenesis and vasodilation. In this study, we hypothesized that CI (by MLD28170) would decrease myocardial apoptosis in the same model.

Calpain inhibition decreases myocardial apoptosis in a swine model of chronic myocardial ischemia.

General use and popularity of over-the-counter supplemental antioxidants have rapidly spread all over the world and are believed to promote cardiovascular health and wellbeing. However, there is a paucity of information and lack of proof that physiological and above-physiological levels of oxidants do harm at the cellular and organismal levels. Instead, several reports demonstrated that reduction in Reactive Oxygen Species (ROS) did not improve vascular function. Interestingly, recent studies show that increased ROS levels play protective role in vascular endothelium and may improve coronary endothelial function. In the current review, we introduce the concept that increased ROS levels, often seen in association with cardiovascular disease, probably is an endothelial-way or 'oxidative response' to cope with vascular pathology.

Antioxidant Therapy: Is it your Gateway to Improved Cardiovascular Health?

Calpain overexpression is implicated in aberrant angiogenesis. We hypothesized that calpain inhibition (MDL28170) would improve collateral perfusion in a swine model with hypercholesterolemia and chronic myocardial ischemia.

Calpain inhibition improves collateral-dependent perfusion in a hypercholesterolemic swine model of chronic myocardial ischemia.

Despite many advances in percutaneous and surgical interventions in the treatment of coronary artery disease (CAD), up to one-third of patients are still either not candidates or receive suboptimal revascularization. Calpains are a class of calcium-activated non-lysosomal cysteine proteases that serve as a proteolytic unit for cellular homeostasis. Uncontrolled activation of calpain has been found to be involved in the pathogenesis of myocardial reperfusion injury, cardiac hypertrophy, myocardial stunning and cardiac ischemia. Inhibition of calpains has been shown to significantly attenuate myocardial stunning and reduced infarct size after ischemia-reperfusion. Calpain inhibition therefore serves as a potential medical therapy for patients suffering from a number of diseases, including CAD.

Calpains and Coronary Vascular Disease.

Sepsis is known as the presence of a Systemic Inflammatory Response Syndrome (SIRS) in response to an infection. In the USA alone, 750,000 cases of severe sepsis are diagnosed annually. More than 70% of sepsis-related deaths occur due to organ failure and more than 50% of septic patients demonstrate cardiac dysfunction. Patients with sepsis who develop cardiac dysfunction have significantly higher mortality, and thus cardiac dysfunction serves as a predictor of survival in sepsis. We have very little understanding about the mechanisms that result in cardiac dysfunction in the setting of sepsis. At present, the factors involved in sepsis-related cardiac dysfunction are believed to include the following: persistent inflammatory changes in the vascular endothelium and endocardium leading to circulatory and micro vascular changes, increase in endothelial reactive oxygen species (ROS), abnormal endothelium-leukocyte interaction resulting in a feed-forward loop for inflammatory cytokines and ROS, contractile dysfunction of the heart due to autonomic dysregulation, metabolic changes in myocardium leading to impaired oxygen delivery and increased oxygen consumption, mitochondrial dysfunction, and persistent inflammatory signaling. In this review article, we will briefly discuss the clinical challenges and our current understanding of cardiac dysfunction in sepsis. Major focus will be on the pathological changes that occur in vascular endothelium, with an emphasis on endocardium, and how endothelial ROS, impaired endothelium-leukocyte interaction, and microcirculatory changes lead to cardiac dysfunction in sepsis. The importance of the ongoing quest for the clinical biomarkers for cardiac dysfunction will also be discussed.

Endothelial ROS and Impaired Myocardial Oxygen Consumption in Sepsis-induced Cardiac Dysfunction.

Calpains are a 15-member class of calcium activated nonlysosomal neutral proteases which are involved in a broad range of cellular function. Calpains are usually localized to the cytosol and within mitochondria. Calpastatin is an endogenous protein that specifically binds to and inhibits calpain. Overactivation of calpain has been implicated in a number of disease processes of the brain, eyes, heart, lungs, pancreas, kidneys, vascular system and skeletal muscle. Therefore, calpain may serve as a potential therapeutic target for a wide variety of disease processes. This review briefly outlines the current literature regarding the involvement of calpain overactivation in the pathogenesis of almost every organ in the body.

Role of Calpain in Pathogenesis of Human Disease Processes.

Calpain inhibition has an enhancing effect on myocardial perfusion and improves myocardial density by inhibiting glycogen synthase kinase 3β (GSK-3β) and up-regulating downstream signaling pathways, including the insulin/PI3K and WNT/β-catenin pathways, in a pig model of chronic myocardial ischemia in the setting of metabolic syndrome.

Article	Year
Cisplatin-associated nephrotoxicity and pathological events. Contributions to nephrology\| PubMed ID: 15912030	2005
Oxidant stress in renal pathophysiology. Contributions to nephrology\| PubMed ID: 15912032	2005
G protein-coupled receptor Ca2+-linked mitochondrial reactive oxygen species are essential for endothelial/leukocyte adherence. Molecular and cellular biology\| PubMed ID: 17724077	2007
Calpain inhibition decreases myocardial apoptosis in a swine model of chronic myocardial ischemia. Surgery\| PubMed ID: 25991048	2015
Antioxidant Therapy: Is it your Gateway to Improved Cardiovascular Health? Pharmaceutica analytica acta\| PubMed ID: 26005589	2015
Calpain inhibition improves collateral-dependent perfusion in a hypercholesterolemic swine model of chronic myocardial ischemia. The Journal of thoracic and cardiovascular surgery\| PubMed ID: 26478238	2016
Calpains and Coronary Vascular Disease. Circulation journal : official journal of the Japanese Circulation Society\| PubMed ID: 26489456	2016
Endothelial ROS and Impaired Myocardial Oxygen Consumption in Sepsis-induced Cardiac Dysfunction. Journal of intensive and critical care\| PubMed ID: 27135058	2016
Role of Calpain in Pathogenesis of Human Disease Processes. Journal of nature and science\| PubMed ID: 27747292	2016
Calpain inhibition modulates glycogen synthase kinase 3β pathways in ischemic myocardium: A proteomic and mechanistic analysis. The Journal of thoracic and cardiovascular surgery\| PubMed ID: 27986275	2017

M. Ruhul Abid

Biography

JoVE Journal Publications

Other Publications