Abstract
Oxidative stress is the main cause of acute myocardial infarction (AMI), which is related to the disorder of the regulation of Bmal1 on the redox state. HSPB1 form homologous-oxidized HSPB1 (homooxidized HSPB1) to resist oxidative damage via S-thiolated modification. However, it is still unclarified whether there is an interaction between the circadian clock and HSPB1 in myocardial injury. A total of 118 AMI patients admitted and treated in our hospital from Sep. 2019 to Sep. 2020 were selected to detect the plasma HSPB1 expression and the redox state. We divided the AMI patients into three subgroups: morning-onset AMI (5 : 00 am to 8 : 00 am; Am-subgroup, n = 38), noon-onset AMI (12 : 00 pm to 15 : 00; Pm-subgroup, n = 45), and night-onset AMI (20 : 00 pm to 23 : 00 pm; Eve-subgroup, n = 35) according to the circadian rhythm of onset. The Am-subgroup had remarkably higher cardiac troponin I (cTnI), creatine kinase MB (CK-MB), and B-type natriuretic peptide (BNP) but lower left ventricular ejection fraction (LVEF) than the Pm-subgroup and Eve-subgroup. Patients complicated with cardiogenic shock were significantly higher in the Am-subgroup than in the other two groups. The homooxidized HSPB1 in plasma markedly decreased in the Am-subgroup. The HSPB1C141S mutant accelerated H9c2 cell apoptosis, increased reactive oxygen species (ROS), and decreased reduced-glutathione (GSH) and the ratio of reduced-GSH and GSSG during oxidative stress. Importantly, we found that the redox state of HSPB1 was consistent with the oscillatory rhythm of Bmal1 expression in normal C57B/L mice. The circadian rhythm disorder contributed to decrease Bmal1 and homooxidized HSPB1 in cardiomyocytes of C57BL/6 mice. In addition, Bmal1 and homooxidized HSPB1 decreased in neonatal rat cardiomyocytes exposed to H2O2. Knockdown of Bmal1 led to significant attenuation in homooxidized HSPB1 expression, whereas overexpression of Bmal1 increased homooxidized HSPB1 expression in response to H2O2. Our findings indicated that the homooxidized HSPB1 reduced probably the AMI patients' risk of shock and target organ damage, which was associated with Bmal1 regulating the redox state of HSPB1.
Highlights
acute myocardial infarction (AMI) is myocardial necrosis caused by acute, persistent ischemia, and hypoxia of coronary arteries, responsible for 16% of the world’s total deaths [1, 2]
Epidemiological data showed that the incidence of AMI showed a unique “morning peak” circadian rhythm [8, 9], which is related to the dysfunction of reactive oxygen species (ROS) scavenging caused by the decreased function of intracellular antioxidant defense system
We explored the mechanism of AMI from a new perspective of the circadian clock transcription factor Bmal1 regulating the endogenous antioxidant system via homooxidized HSPB1
Summary
AMI is myocardial necrosis caused by acute, persistent ischemia, and hypoxia of coronary arteries, responsible for 16% of the world’s total deaths [1, 2]. The imbalance of the myocardial redox state which induced the oxidative stress was the most important cause of cardiomyocyte dysfunction and injury [3]. Oxidative stress is the direct result affecting the outcome of thrombolytic therapy, angioplasty, and coronary artery bypass grafting in AMI [4]. Epidemiological data showed that the incidence of AMI showed a unique “morning peak” circadian rhythm [8, 9], which is related to the dysfunction of reactive oxygen species (ROS) scavenging caused by the decreased function of intracellular antioxidant defense system.
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