Pharmacological inhibition of PTEN limits myocardial infarct size and improves left ventricular function postinfarction
Pharmacological inhibition of PTEN limits myocardial infarct size and improves left ventricular function postinfarction
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DOI：
10.1152/ajpheart.00915.2009
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发表时间：
2010-04-01
影响因子：
4.8
通讯作者：
Ye, Yumei
中科院分区：
文献类型：
--
作者：
Keyes, Kyle T.;Xu, Jing;Ye, Yumei
Keyes KT，Xu J，Long B，Zhang C，Hu Z，Ye Y.药物抑制PTEN可限制心肌梗死范围并改善梗死后左心室功能。美国生理学杂志心脏循环生理学298：H1198-H1208，2010年。首次发表于2010年1月22日; doi：10.1152/ajpheart.00915.2009。磷酸肌醇3-激酶（PI 3 K）通过磷酸化磷脂酰肌醇（Ptdins）产生Ptdins（3，4，5）P-3介导心肌保护信号。10号染色体上的脂质磷酸酶和张力蛋白同源物（Lipid phosphatase and tensin homolog on chromosome 10，PTEN）通过使Ptdins（3，4，5）P-3去磷酸化而拮抗PI 3 K活性，因此抑制PTEN可增强PI 3 K/Akt信号通路，从而保护心肌免受缺血再灌注（I/R）损伤。在这里，我们研究了1）通过双过氧钒分子[BpV（HOpic）]对PTEN的药理学抑制是否减弱体外模拟I/R（SIR）损伤和2）在缺血之前或之后施用BpV（HOpic）是否限制心肌梗死面积（IS）和改善由梗死引起的心功能障碍。首先，成年大鼠心肌细胞用或不用BpV（HOpic）处理，然后暴露于SIR。第二，麻醉大鼠在缺血前或缺血后接受BpV（HOpic）。再灌注4 h时测定IS，再灌注28 d时超声心动图评价左室功能。结果，BpV（HOpic）减少细胞死亡，提高3-[4，5-yl]-2，5-diphenyltetrazolium bromide（MTT）活力，并减少暴露于SIR的细胞凋亡。BpV（HOpic）的这些保护作用与磷酸化Akt增加和caspase-3活性抑制有关。第二，给予BpV（HOpic）显著减少I/R损伤后的IS并抑制caspase-3活性，从而改善梗死后28天的心功能。BpV（HOpic）的这些有益作用归因于Akt/内皮型一氧化氮合酶（eNOS）、ERK 1/2和钙依赖型一氧化氮合酶活性的磷酸化的心肌水平的增加。总之，药理学抑制PTEN通过上调PI 3 K/Akt/eNOS/ERK促生存通路保护I/R损伤，这提示了对抗I/R损伤的新的治疗策略。
Keyes KT, Xu J, Long B, Zhang C, Hu Z, Ye Y. Pharmacological inhibition of PTEN limits myocardial infarct size and improves left ventricular function postinfarction. Am J Physiol Heart Circ Physiol 298: H1198-H1208, 2010. First published January 22, 2010; doi: 10.1152/ajpheart.00915.2009.-Phosphoinositide 3-kinase (PI3K) mediates myocardium protective signaling through phosphorylation of phosphatidylinositol (Ptdins) to produce Ptdins(3,4,5)P-3. Lipid phosphatase and tensin homolog on chromosome 10 ( PTEN) antagonizes PI3K activity by dephosphorylating Ptdins(3,4,5) P-3; therefore, the inhibition of PTEN enhances PI3K/Akt signaling and could prevent myocardium from ischemia-reperfusion (I/R) injury. Here we studied 1) whether the pharmacological inhibition of PTEN by bisperoxovanadium molecules [BpV(HOpic)] attenuates simulated I/R (SIR) injury in vitro and 2) whether the administration of BpV(HOpic) either before or after ischemia limits myocardial infarct size (IS) and ameliorates cardiodysfunction caused by infarction. First, adult rat cardiomyocytes were treated with or without BpV(HOpic) and then exposure to SIR. Second, anesthetized rats received BpV(HOpic) either before or after ischemia. IS was assessed at 4 h reperfusion, and left ventricular function was evaluated by echocardiography at 28 days postreperfusion. As a result, BpV(HOpic) decreased cell death, improved 3-[4,5-yl]-2,5-diphenyltetrazolium bromide (MTT) viability, and reduced apoptosis in cells exposed to SIR. These protective effects of BpV(HOpic) are associated with increased phospho-Akt and the repression of caspase-3 activity. Second, the administration of BpV(HOpic) significantly reduced IS and suppressed caspase-3 activity following I/R injury and consequentially improved cardiac function at 28 day postinfarction. These beneficial effects of BpV( HOpic) are attributed to increases in myocardial levels of phosphorylation of Akt/endothelial nitric oxide synthase (eNOS), ERK1/2, and calcium-dependent nitric oxide synthase activity. In conclusion, the pharmacological inhibition of PTEN protects against I/R injury through the upregulation of the PI3K/Akt/eNOS/ERK prosurvival pathway, suggesting a new therapeutic strategy to combat I/R injury.