Activated Protein C Strengthens Cardiac Tolerance to Ischemic Insults in Aging.
Activated Protein C Strengthens Cardiac Tolerance to Ischemic Insults in Aging.
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DOI：
10.1161/circresaha.121.319044
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发表时间：
2022-01-21
影响因子：
20.1
通讯作者：
Li J
中科院分区：
文献类型：
--
作者：
Ren D;Fedorova J;Davitt K;Van Le TN;Griffin JH;Liaw PC;Esmon CT;Rezaie AR;Li J
活化蛋白C（APC）是一种血浆丝氨酸蛋白酶，具有抗凝和抗炎活性。内皮蛋白C受体（EPCR）与APC的活性相关，并介导其下游信号传导事件。APC在缺血和再灌注（I/R）期间发挥心脏保护作用。本研究的目的是表征APC-EPCR轴在老龄缺血性损伤中的作用。使年轻（3-4个月）和年老（24-26个月）野生型C57 BL/6 J小鼠以及不能与APC相互作用的EPCR点突变（EPCRR 84 A/R84 A）敲入C57 BL/6 J小鼠及其同窝出生的野生型C57 BL/6 J小鼠经受I/R。在再灌注前给予野生型APC、信号选择性APC-2Cys或抗凝剂选择性APC-E170 A。结果表明，心脏I/R降低APC活性，APC活性在老年人与年轻人相比受损，可能归因于EPCR水平随年龄增长而下降。血清EPCR检测结果表明，I/R引发的EPCR脱落进入循环，而APC的管理减弱I/R诱导的EPCR脱落在年轻和老年人的心脏。随后的超声心动图显示，APC和APC-2Cys而不是APC-E170 A改善了年轻和老年小鼠I/R期间的心功能障碍。重要的是，APC通过稳定EPCR提高了老年心脏对缺血损伤的抵抗力。然而，APC的所有这些心脏保护作用在EPCRR 84 A/R84 A小鼠中与其野生型同窝小鼠相比均减弱。离体工作心脏和代谢组学结果表明，AMP激活的蛋白激酶（AMPK）介导的急性适应性反应，而蛋白激酶B（AKT）参与慢性代谢编程与APC治疗的心脏。I/R应激导致心脏中的膜EPCR脱落，并且施用APC防止I/R诱导的心脏EPCR脱落，这对于限制衰老中的心脏损伤至关重要。
Activated protein C (APC) is a plasma serine protease with anticoagulant and anti-inflammatory activities. Endothelial protein C receptor (EPCR) is associated with APC’s activity and mediates its downstream signaling events. APC exerts cardioprotective effects during ischemia and reperfusion (I/R). This study aims to characterize the role of the APC-EPCR axis in ischemic insults in aging. Young (3–4 months) and aged (24–26 months) wild type C57BL/6J mice, as well as EPCR point mutation (EPCRR84A/R84A) knock-in C57BL/6J mice incapable of interaction with APC and its wild type of littermate C57BL/6J mice, were subjected to I/R. Wild type APC, signaling-selective APC-2Cys, or anticoagulant-selective APC-E170A were administrated before reperfusion. The results demonstrated that cardiac I/R reduces APC activity, and the APC activity was impaired in the aged versus young hearts possibly attributable to the declined EPCR level with aging. Serum EPCR measurement showed that I/R triggered the shedding of membrane EPCR into circulation, while administration of APC attenuated the I/R-induced EPCR shedding in both young and aged hearts. Subsequent echocardiography showed that APC and APC-2Cys but not APC-E170A ameliorated cardiac dysfunction during I/R in both young and aged mice. Importantly, APC elevated the resistance of the aged heart to ischemic insults through stabilizing EPCR. However, all these cardioprotective effects of APC were blunted in the EPCRR84A/R84A mice versus its wild-type littermates. The ex vivo working heart and metabolomics results demonstrated that AMP-activated protein kinase (AMPK) mediates acute adaptive response while protein kinase B (AKT) is involved in chronic metabolic programming in the hearts with APC treatment. I/R stress causes shedding of the membrane EPCR in the heart, and administration of APC prevents I/R-induced cardiac EPCR shedding that is critical for limiting cardiac damage in aging.