The role of PI3Kα isoform in cardioprotection.
The role of PI3Kα isoform in cardioprotection.
复制标题
DOI：
10.1007/s00395-017-0657-7
复制
发表时间：
2017-10-17
影响因子：
9.5
通讯作者：
Yellon DM
中科院分区：
文献类型：
--
作者：
Rossello X;Riquelme JA;He Z;Taferner S;Vanhaesebroeck B;Davidson SM;Yellon DM
缺血预处理（IPC）通过激活PI3K-Akt信号级联限制心肌梗死的大小；然而，人们对PI3K亚型在心脏保护中的作用知之甚少。因此，我们的目的是阐明PI3Kα亚型在心脏保护中的作用。我们在缺血/再灌注损伤（IRI）的离体灌注小鼠心脏中评估了PI3Kα的药理学抑制作用，无论是在IPC过程中还是在再灌注时。PI3Kα抑制可消除IPC诱导的再灌注保护作用，但仅在IPC方案中给予时不会。这些结果在体内模型中得到证实。此外，胰岛素在再灌注时的PI3Kα药理激活足以赋予心脏抗IRI保护。此外，PI3Kα在小鼠心肌细胞、小鼠心脏内皮细胞以及小鼠和人心脏组织中表达和活化。此外，PI3Kα通过抑制线粒体通透性过渡孔打开介导其作用。综上所述，在早期再灌注阶段，PI3Kα活性是减少心肌梗死面积所必需的。这表明，在再灌注时特异性增强PI3K α亚型的策略可促进组织挽救，并可为IRI的临床治疗提供直接靶点。本文的在线版本（doi:10.1007/s00395-017-0657-7）包含补充材料，仅供授权用户使用。
Ischemic preconditioning (IPC) limits myocardial infarct size through the activation of the PI3K–Akt signal cascade; however, little is known about the roles of individual PI3K isoforms in cardioprotection. We aimed, therefore, to elucidate the role of the PI3Kα isoform in cardioprotection Pharmacological PI3Kα inhibition was assessed in isolated-perfused mouse hearts subjected to ischemia/reperfusion injury (IRI), either during the IPC procedure or at reperfusion. PI3Kα inhibition abrogated the IPC-induced protective effect at reperfusion, but not when given only during the IPC protocol. These results were confirmed in an in vivo model. Moreover, pharmacological PI3Kα activation by insulin at reperfusion was sufficient to confer cardioprotection against IRI. In addition, PI3Kα was shown to be expressed and activated in mouse cardiomyocytes, mouse cardiac endothelial cells, as well as in mouse and human heart tissue. Furthermore, PI3Kα was shown to mediate its effect though the inhibition of mitochondrial permeability transition pore opening. In conclusion, PI3Kα activity is required during the early reperfusion phase to reduce myocardial infarct size. This suggests that strategies specifically enhancing the α isoform of PI3K at reperfusion promote tissue salvage and as such, and could provide a direct target for clinical treatment of IRI. The online version of this article (doi:10.1007/s00395-017-0657-7) contains supplementary material, which is available to authorized users.
登录
查看更多内容
DOI：
10.1016/s0022-2828(02)00310-3
发表时间：
2003-02-01
影响因子：
5
作者：
Bell, RM;Yellon, DM
通讯作者：
Yellon, DM
影响因子：
64.5
作者：
Knight, Zachary A.;Gonzalez, Beatriz;Shokat, Kevan M.
通讯作者：
Shokat, Kevan M.
影响因子：
--
作者：
Ghigo, Alessandra;Morello, Fulvio;Hirsch, Emilio
通讯作者：
Hirsch, Emilio
影响因子：
7.3
作者：
Ciraolo E;Iezzi M;Marone R;Marengo S;Curcio C;Costa C;Azzolino O;Gonella C;Rubinetto C;Wu H;Dastrù W;Martin EL;Silengo L;Altruda F;Turco E;Lanzetti L;Musiani P;Rückle T;Rommel C;Backer JM;Forni G;Wymann MP;Hirsch E
通讯作者：
Hirsch E
影响因子：
37.8
作者：
Lu Z;Jiang YP;Wang W;Xu XH;Mathias RT;Entcheva E;Ballou LM;Cohen IS;Lin RZ
通讯作者：
Lin RZ