Roles of HDAC3-orchestrated circadian clock gene oscillations in diabetic rats following myocardial ischaemia/reperfusion injury

Abstract

The circadian clock is closely related to the development of diabetes mellitus and cardiovascular disease, and disruption of the circadian clock exacerbates myocardial ischaemia/reperfusion injury (MI/RI). HDAC3 is a key component of the circadian negative feedback loop that controls the expression pattern of the circadian nuclear receptor Rev-erbα to maintain the stability of circadian genes such as BMAL1. However, the mechanism by which the HDAC3-orchestrated Rev-erbα/BMAL1 pathway increases MI/RI in diabetes and its relationship with mitophagy have yet to be elucidated. Here, we observed that the clock genes Rev-erbα, BMAL1, and C/EBPβ oscillations were altered in the hearts of rats with streptozotocin (STZ)-induced diabetes, with upregulated HDAC3 expression. Oscillations of Rev-erbα and BMAL1 were rapidly attenuated in diabetic MI/R hearts versus non-diabetic I/RI hearts, in accordance with impaired and rhythm-disordered circadian-dependent mitophagy that increased injury. Genetic knockdown of HDAC3 significantly attenuated diabetic MI/RI by mediating the Rev-erbα/BMAL1 circadian pathway to recover mitophagy. Primary cardiomyocytes with or without HDAC3 siRNA and Rev-erbα siRNA were exposed to hypoxia/reoxygenation (H/R) in vitro. The expression of HDAC3 and Rev-erbα in cardiomyocytes was increased under high-glucose conditions compared with low-glucose conditions, with decreased BMAL1 expression and mitophagy levels. After H/R stimulation, high glucose aggravated H/R injury, with upregulated HDAC3 and Rev-erbα expression and decreased BMAL1 and mitophagy levels. HDAC3 and Rev-erbα siRNA can alleviate high glucose-induced and H/R-induced injury by upregulating BMAL1 to increase mitophagy. Collectively, these findings suggest that disruption of HDAC3-mediated circadian gene expression oscillations induces mitophagy dysfunction, aggravating diabetic MI/RI. Cardiac-specific HDAC3 knockdown could alleviate diabetic MI/RI by regulating the Rev-erbα/BMAL1 pathway to restore the activation of mitophagy.

The critical roles of histone deacetylase 3 in the pathogenesis of solid organ injury

“…Intriguingly, the levels of Rev-erbα and BMAL1 displayed opposite rhythm after ischemia-reperfusion stimulation in diabetic rats. Subsequent studies showed that HDAC3 aggravated diabetic MI in rats by altering the oscillations of circadian genes, thereby causing mitophagy dysfunction in cardiomyocytes [ 15 ]. Interestingly, hyperglycemia significantly increased HDAC3 protein levels.…”

“…1A ) [ 14 ]. Mounting evidence suggests that HDAC3 plays a key role in solid organ injury [ 15 – 17 ]. In this review article, we provide an overview of the current knowledge of the role of HDAC3 in the pathogenesis of solid organ injury, focusing on the possible underlying molecular mechanisms.…”

Ischemic Postconditioning-Mediated DJ-1 Activation Mitigate Intestinal Mucosa Injury Induced by Myocardial Ischemia Reperfusion in Rats Through Keap1/Nrf2 Pathway

“…All animals were fasted but had free access to water for 12 h before the experiments. We used the model of myocardial IR injury as described previously (Qiu et al, 2017(Qiu et al, , 2021Zhou et al, 2017;Li et al, 2020) in which the rats were anesthetized completely and subjected to myocardial IR by clamping the left anterior descending coronary artery (LAD) for 30 min followed by reperfusion for 120 min. A ligature was placed ∼2 mm below the branch of the LAD with a 6-0 lesion-free line for ligation.…”

Advances in Cardiotoxicity Induced by Altered Mitochondrial Dynamics and Mitophagy

“…It is a form of a mitochondrial outer membrane protein with a biphasic effect. The phosphorylation of their microtubule-associated protein 1A/1B-light chain 3 (LC3)-interacting region (LIR) binds to LC3-phosphatidylethanolamine conjugate light chain 3 (LC3II), which is involved in mitophagy and plays a significant role in myocardial mitochondrial regeneration ( 24 , 87 – 89 ). The hypoxia inducible factor 1 subunit alpha (HIF-1α) can bind to the BNIP3 promoter to induce BNIP3, and BNIP3 expression can also promote PINK1 translocation, and then induce mitophagy ( 90 ).…”

“…Moreover, oxidative stress reactions can also activate mitophagy through BNIP3/NIX and ROS promotes BNIP3 expression by activating the HIF-1α, which subsequentially induces mitophagy ( 89 , 90 ). Reportedly, the oxidative stress response is a crucial cause of mitophagy disorders in diabetic patients ( 24 ). In addition, membrane associated Ring-CH-Type Finger 5 (MARCHF5) and cellular communication network factor 1 (CCN1/Cyr61) are protein molecules located in the mitochondrial outer membrane, these proteins also play a vital role in the autophagy process of mitochondria, reducing expression during oxidative stress, and further inhibits mitophagy ( 173 , 174 ).…”