Roles of HDAC3-Orchestrated Circadian Clock Gene Oscillations in Diabetic Rats Following Myocardial Ischemia / Reperfusion Injury

Abstract

Background: Circadian clock has been closely related to the development of diabetes mellitus and cardiovascular disease; the disruption of circadian clock exacerbates myocardial ischemia/reperfusion injury (MI/RI). HDAC3 is a key component of the circadian negative feedback loop by recruitmenting the expression pattern of circadian nuclear receptor Rev-erbα, then to maintain the stability of circadian gene such as BMAL1. In this research, we explored the mechanism of HDAC3-orchestrated Rev-erbα/BMAL1 pathway in increasing MI/RI vulnerability of diabetes, and its relationship with mitophagy. Methods and results: Streptozocin (STZ) was used to establish type 1 diabetes by intraperitoneal injection. After 8 weeks, the diabetic and non-diabetic rats were exposed to MI/RI by ligating the left anterior descending coronary artery (LDA) for 30 minutes and reperfusion for 120 minutes at four time points of zeitgeber (ZT) 0, 6, 12 and 18. Circadian clock gene oscillations were rapidly attenuated in diabetic I/RI hearts, versus sham and/or the non-diabetic I/RI hearts, in accord with circadian mitophagy. By utilizing AAV-HDAC3 to knockdown HDAC3 expression, HDAC3 deficiency significantly attenuated diabetic MI/RI associated with increased autophagy activation. In vitro experiments, primary cardiomyocytes with or without HDAC3 siRNA and Rev-erbα siRNA exposed to hypoxia/reoxygenation (H/R). The expression of HDAC3 and Rev-erbα in cardiomyocytes was increased under high glucose condition with decreased BMAL1 expression and autophagy level. After H/R stimulation, the cell injury was obviously increased with upregulated HDAC3 and Rev-erbα expression and decreased BMAL1 level. Moreover, high glucose aggravated H/R injury compared with low glucose by reducing autophagy level, increasing the levels of HDAC3 and Rev-erbα and down-regulating BMAL1 expression. HDAC3 and Rev-erbα siRNA can alleviate high glucose and H/R-induced injury by up-regulating BMAL1 expression and mitophagy levels. Conclusion: These findings suggest that in diabetic rat MI/RI , the circadian clocks were rapidly impaired then to inhibit mitophagy; cardiac-targeted manipulation of HDAC3-orchestrated Rev-erbα/BMAL1 pathway may be the mechanism of the decreased toleration to ischemia with a circadian dependent variability.

Nogo-A mediated endoplasmic reticulum stress during myocardial ischemic-reperfusion injury in diabetic rats

“…While timely reperfusion has proved to be an invaluable tool, MI/R injury represents a mechanism that may limit its effectiveness. We and others have previously shown that the diabetic myocardium is more susceptible to ischemia-reperfusion injury, possible causes are increased oxidative stress, inflammation response, apoptosis, ER stress or mitochondrial dysfunction, but further mechanisms are still to be studied (Leng, et al 2018;Samidurai, et al 2020;Qiu, et al 2021). ER stress is an important feature leading to the cardiac dysfunction after ischemic heart diseases in diabetes.…”

Patients with Subarachnoid Hemorrhage Exhibit Disturbed Expression Patterns of the Circadian Rhythm Gene Period-2

“…Circadian rhythmicity has been shown to be altered in the hippocampus, as well as other brain and peripheral tissues, in response to ischemia [ 18 ]. While ischemia itself impacts circadian rhythmicity, quantitative expression of circadian genes like Per , CLOCK and BMAL1 at the time of injury is in turn relevant for the extent of ischemic damage that is sustained by the affected tissue [ 19 , 20 ]. SAH inflicts not only hemorrhagic cerebral damage, especially in close proximity to CNS areas with circadian pacemaker function, but also ischemic damage both at disease onset via increased intracranial pressure, and during the disease course in the form of micro-thrombosis and delayed cerebral ischemia.…”