Attenuation of myocardial injury in mice with functional deletion of the circadian rhythm gene mPer2.
Attenuation of myocardial injury in mice with functional deletion of the circadian rhythm gene mPer2.
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DOI：
10.1152/ajpheart.01280.2008
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发表时间：
2010-03
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通讯作者：
Jitka A I Virag;Jessica L. Dries;Peter R Easton;A. Friesland;Jonathan H. DeAntonio;Vishnu Chintalgattu;E. Cozzi;B. Lehmann;Jian M. Ding;R. Lust
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作者：
Jitka A I Virag;Jessica L. Dries;Peter R Easton;A. Friesland;Jonathan H. DeAntonio;Vishnu Chintalgattu;E. Cozzi;B. Lehmann;Jian M. Ding;R. Lust
昼夜节律的变化在心血管疾病的发病率中是明显的，当节律被打乱时，心血管事件的风险会增加。视交叉上核是调节周围器官日常节律的中央昼夜节律起搏器。昼夜节律最近被证明存在于心肌组织中，并与代谢和收缩功能有关。因此，我们试图确定昼夜节律小鼠周期基因2 （mPer2）的功能性缺失是否会保护心脏免受缺血性损伤。在麻醉、通气的C57 （n = 17）和mPer2突变体（mPer2- m; n = 15）小鼠中，通过永久性结扎左冠状动脉前降支诱导非再灌注心肌梗死。心肌梗死后4天，我们观察到mPer2-M小鼠的梗死面积比野生型小鼠减少43%。与此同时，梗死区巨噬细胞浸润减少25%，毛细血管密度增加43%，肥厚增加17%，心肌细胞凋亡减少15%。此外，基质金属蛋白酶-9在两组的炎症细胞中均有表达，但野生型小鼠的总蛋白含量高出40%，而mPer2-M小鼠在损伤反应中没有升高。mPer2基因的功能性缺失通过限制炎症反应、减少细胞凋亡、诱导心肌细胞肥厚，从而降低心肌梗死损伤的严重程度，从而保持心功能。这些发现共同表明，生物钟基因mPer2的破坏具有保护作用。了解昼夜节律基因与心血管疾病之间的相互作用可能为易感人群提供潜在的预防和治疗策略。
Variations in circadian rhythms are evident in the incidence of cardiovascular disease, and the risk of cardiovascular events increases when rhythms are disrupted. The suprachiasmatic nucleus is the central circadian pacemaker that regulates the daily rhythm of peripheral organs. Diurnal rhythms have more recently been shown to exist in myocardial tissue and are involved in metabolism and contractile function. Thus we sought to determine whether the functional deletion of the circadian rhythm mouse periodic gene 2 (mPer2) would protect the heart against ischemic injury. Nonreperfused myocardial infarction was induced in anesthetized, ventilated C57 (n = 17) and mPer2 mutant (mPer2-M; n = 15) mice via permanent ligation of the left anterior descending coronary artery. At 4 days post-myocardial infarction, we observed a 43% reduction of infarct area in mPer2-M mice compared with wild-type mice. This is coincident with 25% less macrophage infiltration, 43% higher capillary density, 17% increase in hypertrophy, and 15% less cardiomyocyte apoptosis in the infarct zone. Also, matrix metalloproteinase-9 was expressed in inflammatory cells in both groups, but total protein was 40% higher in wild-type mice, whereas it was not elevated in mPer2-M mice in response to injury. The functional deletion of the mPer2 gene reduces the severity of myocardial infarct injury by limiting the inflammatory response, reducing apoptosis, and inducing cardiomyocyte hypertrophy, thus preserving cardiac function. These findings collectively imply that the disruption of the circadian clock gene mPer2 is protective. Understanding the interactions between circadian rhythm genes and cardiovascular disease may provide insights into potential preventative and therapeutic strategies for susceptible populations.