Protease-activated receptors and myocardial infarction.
Protease-activated receptors and myocardial infarction.
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DOI：
10.1002/iub.441
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发表时间：
2011-06
期刊：
影响因子：
4.6
通讯作者：
Mackman, Nigel
中科院分区：
文献类型：
--
作者：
Antoniak, Silvio;Pawlinski, Rafal;Mackman, Nigel
蛋白酶激活受体（PARs）在心脏内广泛表达。它们被无数的蛋白酶激活，包括凝血蛋白酶。体外研究表明，PAR-1和PAR-2对心肌细胞的激活可诱导心肌肥大。此外，PAR-1刺激心脏成纤维细胞可诱导增殖。遗传学和药理学方法已被用于研究不同的PARs在心脏缺血/再灌注（I/R）损伤中的作用。据报道，在小鼠和大鼠中，PAR-1在心脏I/R损伤后的炎症、梗死面积和重塑中发挥作用。然而，PAR-1缺乏和PAR-1抑制的效果有显著差异。例如，抑制PAR-1可减少梗死面积，而缺乏PAR-1则没有影响。这些差异可能是由于抑制剂的脱靶效应或PAR-4对PAR-1缺乏症的补偿。同样，在I/R损伤后，PAR-2的缺乏与心脏炎症的减少和心脏功能的改善有关，而PAR-2的药理激活由于血管舒张增加而被发现具有保护作用。这些差异可能是由于内源性蛋白酶和外源性激动剂肽诱导的不同信号反应。令人惊讶的是，PAR-4缺乏导致I/R损伤后心脏损伤增加和死亡率增加。相反，药理学研究表明抑制PAR-4对心脏有保护作用。有可能PAR-4抑制剂的主要细胞靶点是血小板，血小板已被证明有助于损伤心脏的炎症，而心肌细胞中的PAR-4信号可能具有保护作用。遗传和药理学方法之间的差异表明，需要进一步的研究来确定不同的PARs在损伤心脏中的作用。
Protease activated receptors (PARs) are widely expressed within the heart. They are activated by a myriad of proteases, including coagulation proteases. In vitro studies showed that activation of PAR-1 and PAR-2 on cardiomyocytes induced hypertrophy. In addition, PAR-1 stimulation on cardiac fibroblasts induced proliferation. Genetic and pharmacologic approaches have been used to investigate the role of the different PARs in cardiac ischemia/reperfusion (I/R) injury. In mice and rats PAR-1 is reported to play a role in inflammation, infarct size and remodeling after cardiac I/R injury. However, there are notable differences between the effect of a deficiency in PAR-1 and inhibition of PAR-1. For instance, inhibition of PAR-1 reduced infarct size whereas there was no effect of a deficiency of PAR-1. These differences maybe due to off-target effects of the inhibitor or PAR-4 compensation of PAR-1 deficiency. Similarly, a deficiency of PAR-2 was associated with reduced cardiac inflammation and improved heart function after I/R injury, whereas pharmacologic activation of PAR-2 was found to be protective due to increased vasodilatation. These differences maybe due to different signaling responses induced by an endogenous proteases versus an exogenous agonist peptide. Surprisingly, PAR-4 deficiency resulted in increased cardiac injury and increased mortality after I/R injury. In contrast, a pharmacological study indicated that inhibition of PAR-4 was cardioprotective. It is possible that the major cellular target of the PAR-4 inhibitor is platelets, which have been shown to contribute to inflammation in the injured heart, whereas PAR-4 signaling in cardiomyocytes may be protective. These discrepant results between genetic and pharmacological approaches indicate that further studies are needed to determine the role of different PARs in the injured heart.
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