Murine Model of Wound Healing

Wound healing and repair are the most complex biological processes that occur in human life. After injury, multiple biological pathways become activated. ...

The Heart Research Institute

University of Sydney 

High-density lipoproteins (HDL) and their main apolipoprotein, apoA-I, exhibit anti-inflammatory properties. The development of peptides that mimic HDL apolipoproteins offers a promising strategy to reduce inflammatory disease. This study aimed to compare the anti-inflammatory effects of ETC-642, an apoA-I mimetic peptide, with that of discoidal reconstituted HDL (rHDL), consisting of full-length apoA-I complexed with phosphatidylcholine, in rabbits with chronic vascular inflammation.

The apolipoprotein A-I mimetic peptide, ETC-642, reduces chronic vascular inflammation in the rabbit.

Lipoprot&eacute;ines de haute densit&eacute; (HDL) et leur principaux apolipoprot&eacute;ine, apoA-I, pr&eacute;sentent des propri&eacute;t&eacute;s anti-inflammatoires. Le d&eacute;veloppement de peptides qui imitent les HDL apolipoprot&eacute;ines propose une strat&eacute;gie prometteuse pour r&eacute;duire les maladies inflammatoires. Cette &eacute;tude visait &agrave; comparer les effets anti-inflammatoires de l&#39;apoA, etc.-642-j&#39;ai des peptides mim&eacute;tiques, avec celui de la disco&iuml;dale HDL reconstitu&eacute; (rHDL), consistant en pleine longueur apoA-j&#39;ai complex&eacute; avec la phosphatidylcholine, chez les lapins avec une inflammation vasculaire chronique.

L&#39;apolipoprot&eacute;ine A-I peptides mim&eacute;tiques, etc.-642, r&eacute;duit l&#39;inflammation vasculaire chronique chez le lapin.

Lipoproteine ad alta densit&agrave; (HDL) e loro principali Apolipoproteine, apoA-I, presentano propriet&agrave; anti-infiammatorie. Lo sviluppo di peptidi che mimano HDL Apolipoproteine offre una strategia promettente per ridurre la malattia infiammatoria. Questo studio mira a confrontare gli effetti anti-infiammatori di ecc-642, un apoA-I peptide mimetico, con quello di HDL ricostituita trilobozoi (rHDL), costituito da full-length apoA-I complessati con fosfatidilcolina, in conigli con l&#39;infiammazione vascolare cronica.

Apolipoproteina A-I peptide mimetico, ecc-642, riduce l&#39;infiammazione vascolare cronica nel coniglio.

The inflammatory chemokines CCL2, CCL5, and CXâ‚ƒCL1 stimulate vascular smooth muscle cell (SMC) proliferation. High-density lipoproteins (HDLs) exhibit potent cardioprotective and anti-inflammatory properties. We therefore sought to determine the effect of reconstituted HDLs (rHDLs) on SMC chemokine expression and proliferation and elucidate the mechanisms. Preincubation of primary human SMCs with rHDLs containing apolipoprotein (apo)A-I and phosphatidylcholine (20 Î¼M, final apoA-I concentration), before stimulation with TNF-Î±, inhibited CCL2 (54%), CCL5 (38%), and CX3CL1 (33%) protein levels. The chemokine receptors CCR2 (29%) and CX3CR1 (22%) were also reduced by rHDLs. Incubation with rHDLs reduced the NF-ÎºB subunit p65 in the nucleus (39%) and phosphorylated IÎºBÎ± (28%), both regulators of chemokine expression. Furthermore, rHDLs inhibited the upstream signaling proteins phosphoinositide 3-kinase (37%) and phosphorylated Akt (pAkt, 49%). Incubation with rHDLs strikingly suppressed SMC proliferation (84%) and ERK phosphorylation (pERK, 29%). Finally, siRNA knockdown of the scavenger receptor SR-B1 attenuated rHDL-induced inhibition of SMC chemokine expression, p65, and proliferation, indicating that SR-B1 plays a key role in mediating these effects. Thus, rHDLs reduce SMC chemokine expression (via NF-ÎºB/pAkt inhibition) and proliferation (via pERK inhibition). This has important implications for preventing the pathogenesis of neointimal hyperplasia, the main cause of early vein graft/stent failure.

High-density lipoproteins suppress chemokine expression and proliferation in human vascular smooth muscle cells.

Les chimiokines inflammatoires CCL2, CCL5 et CX&#x2083;CL1 stimuler la prolif&eacute;ration cellulaire (SMC) de muscle lisse vasculaire. Lipoprot&eacute;ines de haute densit&eacute; (HDL) pi&egrave;ce cardioprotecteurs puissant et propri&eacute;t&eacute;s anti-inflammatoires. Nous avons donc cherch&eacute; &agrave; d&eacute;terminer l&#39;effet d&#39;HDL reconstitu&eacute; (rHDLs) sur l&#39;expression de chemokine SMC et de prolif&eacute;ration et d&#39;&eacute;lucider les m&eacute;canismes. Pr&eacute;incubation des primaires CML humaine avec rHDLs contenant apolipoprot&eacute;ine (apo) A-I et la phosphatidylcholine (20 &mu;M, apoA final-je concentration), avant que la stimulation avec le TNF-&alpha;, inhib&eacute;e CCL2 (54 %), CCL5 (38 %) et CX3CL1 taux de prot&eacute;ines (33 %). Les r&eacute;cepteurs de chimiokine CCR2 (29 %) et CX3CR1 (22 %) ont &eacute;galement &eacute;t&eacute; r&eacute;duits par rHDLs. L&#39;incubation avec rHDLs r&eacute;duit le NF-&kappa;B sous-unit&eacute; p65 dans le noyau (39 %) et phosphoryl&eacute;e I&kappa;B&alpha; (28 %), les deux r&eacute;gulateurs de chemokine expression. Par ailleurs, rHDLs a inhib&eacute; l&#39;amont signalisation prot&eacute;ines phosphoinositide 3-kinase (37 %) et phosphoryl&eacute; Akt (pAkt, 49 %). Incubation avec rHDLs supprim&eacute;e remarquablement prolif&eacute;ration SMC (84 %) et la phosphorylation de ERK (pERK, 29 %). Enfin, siARN knockdown du r&eacute;cepteur &eacute;boueur SR-B1 a att&eacute;nu&eacute; rHDL induite par l&#39;inhibition de la SMC chemokine expression, p65 et prolif&eacute;ration, ce qui indique que SR-B1 joue un r&ocirc;le cl&eacute; dans la m&eacute;diation de ces effets. Ainsi, rHDLs r&eacute;duire expression chemokine SMC (via l&#39;inhibition de NF-&kappa;B/pAkt) et la prolif&eacute;ration (via l&#39;inhibition pERK). Ceci a des implications importantes pour la pr&eacute;vention de la pathogen&egrave;se de l&#39;hyperplasie n&eacute;ointimale, la principale cause d&#39;&eacute;chec de greffe/stent veine pr&eacute;coce.

Lipoprot&eacute;ines de haute densit&eacute; r&eacute;primer l&#39;expression de chimiokines et prolif&eacute;ration de cellules musculaires lisses vasculaires humaines.

Le chemochine infiammatorie CCL2, CCL5 e CX&#x2083;CL1 stimolare la proliferazione cellulare (SMC) muscolatura liscia vascolare. Lipoproteine ad alta densit&agrave; (HDL) presentano propriet&agrave; anti-infiammatorie e cardioprotettivi potente. Quindi abbiamo cercato di determinare l&#39;effetto di HDL ricostituita (rHDLs) sull&#39;espressione delle chemochine SMC e proliferazione e delucidare i meccanismi. Preincubazione di SMCs umano primario con rHDLs contenenti apolipoproteina (apo) A-I e fosfatidilcolina (20 &mu;M, finale apoA-I concentrazione), prima che la stimolazione con TNF-&alpha;, inibito CCL2 (54%), CCL5 (38%) e CX3CL1 livelli di proteine (33%). I recettori delle chemochine CCR2 (29%) e CX3CR1 (22%) sono stati ridotti anche da rHDLs. Incubazione con rHDLs ridotto il NF-&kappa;B subunit&agrave; p65 nel nucleo (39%) e fosforilato I&kappa;B&alpha; (28%), entrambi regolatori dell&#39;espressione delle chemochine. Inoltre, rHDLs inibito l&#39;upstream segnalazione proteine fosfoinositide 3-chinasi (37%) e fosforilata di Akt (Patto, 49%). Incubazione con rHDLs sorprendentemente soppresso SMC proliferazione (84%) e la fosforilazione di ERK (pERK, 29%). Infine, siRNA atterramento del recettore scavenger SR-B1 attenuato rHDL-induced inibizione dell&#39;espressione delle chemochine SMC, p65 e proliferazione, che indica che il SR-B1 svolge un ruolo fondamentale nella mediazione di questi effetti. Cos&igrave;, rHDLs ridurre espressione delle chemochine SMC (tramite inibizione di NF-&kappa;B/patto) e proliferazione (tramite inibizione pERK). Questo ha implicazioni importanti per prevenire la patogenesi dell&#39;iperplasia neointimale, la principale causa del fallimento di innesto/stent precoce vena.

Article	Year
The apolipoprotein A-I mimetic peptide, ETC-642, reduces chronic vascular inflammation in the rabbit. Lipids in health and disease\| PubMed ID: 22128776	2011
High-density lipoproteins suppress chemokine expression and proliferation in human vascular smooth muscle cells. FASEB journal : official publication of the Federation of American Societies for Experimental Biology\| PubMed ID: 23271056	2013

Laura Z. Vanags

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