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PER2 Regulates Reactive Oxygen Species Production in the Circadian Susceptibility to Ischemia/Reperfusion Injury in the Heart

ABSTRACT: The main objective of this study was to investigate the diurnal differences in Period 2 (PER2) expression in myocardial ischemia-reperfusion (I/R) injury. We investigated diurnal variations in oxidative stress and energy metabolism after myocardial I/R in vitro and in vivo. In addition, we also analyzed the effects of H2O2 treatment and serum shock in H9c2 cells transfected with silencing RNA against Per2 (siRNA-Per2) in vitro. We used C57BL/6 male mice to construct a model of I/R injury at zeitgeber time (ZT) 2 and ZT14 by synchronizing the circadian rhythms. Our in vivo analysis demonstrated that there were diurnal differences in the severity of injury caused by myocardial infarctions, with more injury occurring in the daytime. PER2 was significantly reduced in heart tissue in the daytime and was higher at night. Our results also showed that more severe injury of mitochondrial function in daytime produced more reactive oxygen species (ROS) and less ATP, which increased myocardial injury. In vitro, our findings presented a similar trend showing that apoptosis of H9c2 cells was increased when PER2 expression was lower. Meanwhile, downregulation of PER2 disrupted the oxidative balance by increasing ROS and mitochondrial injury. The result was a reduction in ATP and failure to provide sufficient energy protection for cardiomyocytes.

SUBMITTER: Weng Y

PROVIDER: S-EPMC8519710 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Introduction: Elevated levels of mitochondrial reactive oxygen species (ROS) contribute to the development of numerous cardiovascular diseases. TERT, the catalytic subunit of telomerase, has been shown to translocate to mitochondria to suppress ROS while promoting ATP production. Acute overexpression of TERT increases survival and decreases infarct size in a mouse model of myocardial infarct, while decreased telomerase activity predisposes to mitochondrial defects and heart failure. In the present study, we examined the role of TERT on cardiac structure and function under basal conditions and conditions of acute or prolonged stress in a novel rat model of TERT deficiency. Methods: Cardiac structure and function were evaluated via transthoracic echocardiogram. Langendorff preparations were used to test the effects of acute global ischemia reperfusion injury on cardiac function and infarction. Coronary flow and left ventricular pressure were measured during and after ischemia/reperfusion (I/R). Mitochondrial DNA integrity was measured by PCR and mitochondrial respiration was assessed in isolated mitochondria using an Oxygraph. Angiotensin II infusion was used as an established model of systemic stress. Results: No structural changes (echocardiogram) or coronary flow/left ventricle pressure (isolated hearts) were observed in TERT-/- rats at baseline; however, after I/R, coronary flow was significantly reduced in TERT-/- compared to wild type (WT) rats, while diastolic Left Ventricle Pressure was significantly elevated (n = 6 in each group; p < 0.05) in the TERT-/-. Interestingly, infarct size was less in TERT-/- rats compared to WT rats, while mitochondrial respiratory control index decreased and mitochondrial DNA lesions increased in TERT-/- compared to WT. Angiotensin II treatment did not alter cardiac structure or function; however, it augmented the infarct size significantly more in TERT-/- compared to the WT. Conclusion: Absence of TERT activity increases susceptibility to stress like cardiac injury. These results suggest a critical role of telomerase in chronic heart disease.

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PER2 Regulates Reactive Oxygen Species Production in the Circadian Susceptibility to Ischemia/Reperfusion Injury in the Heart

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