PNAS：華中科大廖燕宏研究組與合作者發表心肌缺血再灌注損傷研究論文

2017年5月19日， 國際著名學術期刊《美國科學院院刊》線上發表了華中科技大學基礎醫學院解剖學系廖燕宏教授團隊和阿根廷天主教大學生物醫學研究所Birnbaumer實驗室Lutz Birnbaumer教授共同合作的一篇研究論文， 論文報導了關於心肌缺血再灌注損傷發病機制。 研究論文題目為《TRPC3/6/7對心肌缺血/再灌注損傷和細胞缺氧/複氧損傷的影響》(Major contribution of the 3/6/7 class of TRPC channels to myocardial ischemia/reperfusion and cellular hypoxia / reoxygenation injuries)。 博士研究生賀細菊和李壽田為論文共同第一作者;Lutz Birnbaumer教授和廖燕宏教授為論文的共同通訊作者。

心肌缺血再灌注損傷(Myocardial Ischemia-ReperfusionInjury, MIRI)是指心臟在缺血基礎上， 恢復血供後損傷反而加重， 甚至發生不可逆性心肌損傷。

目前認為引起MIRI 的機制包括：氧自由基合成過多;心肌細胞鈣超載;白細胞在冠脈細小血管內皮細胞處粘附並啟動， 形成新的血栓;ATP合成減少以及內皮素、血管緊張素II的異常表達。 在上述發病機制中， 心肌細胞的鈣超載是啟動 MIRI 發生最關鍵因素之一。 反向鈉鈣交換器(NCX)， L 型鈣通道， SERCA泵和線粒體膜上鈣轉運體(MCU)的異常表達和/或開放， 是 MIRI鈣超載形成的主要鈣離子來源。 本項研究利用TRPC3/6/7基因敲除鼠， 結合心肌H9c2細胞系， 發現經典暫態受體電位(Canonical transient receptor potential, TRPC)的TRPC3/6/7亞類直接參與了MIRI的發生。 在心肌細胞缺血狀態下， TRPC3/6介導的鈣超載， 可引起心肌細胞線粒體損傷及其凋亡。 於此同時， TRPC3/6介導的鈣超載通過NFAT3c途徑， 又增加心肌細胞TRPC3、6 的表達， 引起進一步鈣超載。 TRPC3/6的這種“正回饋”模式， 加劇了MIRI損傷進程。 該研究結果拓寬了對TRPC家族的生理學功能的認識， 為尋找治療和干預MIRI措施提供了新思路。

原文連結：

Major contribution of the 3/6/7 class of TRPC channels to myocardial ischemia/reperfusion and Cellular hypoxia / reoxygenation injuries

原文摘要：

The injury phase after myocardial infarcts occurs during reperfusion and is a consequence of calcium release from internal stores combined with calcium entry, leading to cell death by apoptopic and necrotic processes. The mechanism(s) by which calcium enters cells has(ve) not been identified. Here, we identify canonical transient receptor potential channels (TRPC) 3 and 6 as the cation channels through which most of the damaging calcium enters cells to trigger their death, and we describe mechanisms activated during the injury phase. Working in vitro with H9c2 cardiomyoblasts subjected to 9-h hypoxia followed by 6-h reoxygenation (H/R), and analyzing changes occurring in areas-at-risk (AARs) of murine hearts subjected to a 30-min ischemia followed by 24-h reperfusion (I/R) protocol, we found: (i) that blocking TRPC with SKF96365 significantly ameliorated damage induced by H/R, including development of the mitochondrial permeability transition and proapoptotic changes in Bcl2/BAX ratios; and (ii) that AAR tissues had increased TUNEL+ cells, augmented Bcl2/BAX ratios, and increased p(S240)NFATc3, p(S473)AKT, p(S9)GSK3β, and TRPC3 and -6 proteins, consistent with activation of a positive-feedback loop in which calcium entering through TRPCs activates calcineurin-mediated NFATc3-directed transcription of TRPC genes, leading to more Ca2+ entry. All these changes were markedly reduced in micelacking TRPC3, -6, and -7. The changes caused by I/R in AAR tissues were matched by those seen after H/R in cardiomyoblasts in all aspects except for p-AKT and p-GSK3β, which were decreased after H/R in cardiomyoblasts instead of increased. TRPC should be promising targets for pharmacologic intervention after cardiac infarcts.

作者：廖燕宏 點擊：次