Abstract
High-glucose-induced cardiomyocyte injury is the major cause of diabetic cardiomyopathy, but its regulatory mechanisms are not fully understood. Here, we report that a circadian clock gene, brain and muscle Arnt-like 1 (Bmal1), increases autophagy in high-glucose-induced cardiomyocyte injury. We constructed a hyperglycemia model with cultured cardiomyocytes from neonatal rats. High-glucose-induced inhibition of autophagy and cardiomyocyte injury were attenuated by Bmal1 overexpression and aggravated by its knockdown. Furthermore, autophagy stabilization by 3-methyladenine or rapamycin partially suppressed the effects of altered Bmal1 expression on cardiomyocyte survival. Mechanistically, Bmal1 mediated resistance to high-glucose-induced inhibition of autophagy at least partly by inhibiting mTOR signaling activity. Collectively, our findings suggest that the clock gene Bmal1 is a positive regulator of autophagy through the mTOR signaling pathway and protects cardiomyocytes against high-glucose toxicity.
Highlights
Diabetic cardiomyopathy refers to a disease process that affects the myocardium in the diabetic heart, thereby causing a variety of structural abnormalities and leading to left ventricular hypertrophy and dysfunction [1, 2]
(1) Does the circadian clock gene brain and muscle Arnt-like 1 (Bmal1) impact cardiomyocyte death and survival under high-glucose conditions? (2) How is altered autophagy involved in the impact of altered Bmal1 expression on cardiomyocyte viability in response to high glucose? (3) What is the molecular mechanism underlying the change in autophagy activity in response to alterations in Bmal1 expression? Our results demonstrated that the clock gene Bmal1 regulates autophagy via the mammalian target of rapamycin (mTOR) pathway and protects cardiomyocytes against high-glucose toxicity
Compared with the scrambled control (SC) short hairpin RNA (shRNA) group, knock down (KD) of Bmal1 led to a significant increase in cardiomyocyte death under high-glucose conditions (36.92 ± 4.88% in Bmal1shRNA vs. 24.80 ± 4.88% in SCshRNA, p < 0.01, n = 8; Figure 1A and 1B)
Summary
Diabetic cardiomyopathy refers to a disease process that affects the myocardium in the diabetic heart, thereby causing a variety of structural abnormalities and leading to left ventricular hypertrophy and dysfunction [1, 2]. Current treatments cannot effectively reduce diabetic cardiomyopathy in diabetic patients, indicating that other mechanisms remain to be discovered Numerous studies in both human subjects and animal models have confirmed that perturbations of the internal clock system constitute risk factors for such disorders as obesity, type 2 diabetes, and cardiovascular disease [7,8,9,10,11]. Genetic disruption of Bmal induces an abnormal metabolic phenotype characterized by impaired gluconeogenesis, hyperleptinemia, glucose intolerance, and dyslipidemia [18,19,20]. Given this evidence, we hypothesized that the circadian gene Bmal might participate in the pathogenesis www.impactjournals.com/oncotarget of diabetic cardiomyopathy and that such a connection would furnish new opportunities for mechanism-based diabetic cardiomyopathy therapeutics
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