Omentin1 ameliorates myocardial ischemia-induced heart failure via SIRT3/FOXO3a-dependent mitochondrial dynamical homeostasis and mitophagy

Abstract

Background Adipose tissue-derived adipokines are involved in various crosstalk between adipose tissue and other organs. Omentin1, a novel adipokine, exerts vital roles in the maintenance of body metabolism, insulin resistance and the like. However, the protective effect of omentin1 in myocardial ischemia (MI)-induced heart failure (HF) and its specific mechanism remains unclear and to be elucidated. Methods The model of MI-induced HF mice and oxygen glucose deprivation (OGD)-injured cardiomyocytes were performed. Mice with overexpression of omentin1 were constructed by a fat-specific adeno-associated virus (AAV) vector system. Results We demonstrated that circulating omentin1 level diminished in HF patients compared with healthy subjects. Furthermore, the fat-specific overexpression of omentin1 ameliorated cardiac function, cardiac hypertrophy, infarct size and cardiac pathological features, and also enhanced SIRT3/FOXO3a signaling in HF mice. Additionally, administration with AAV-omentin1 increased mitochondrial fusion and decreased mitochondrial fission in HF mice, as evidenced by up-regulated expression of Mfn2 and OPA1, and downregulation of p-Drp1(Ser616). Then, it also promoted PINK1/Parkin-dependent mitophagy. Simultaneously, treatment with recombinant omentin1 strengthened OGD-injured cardiomyocyte viability, restrained LDH release, and enhanced the mitochondrial accumulation of SIRT3 and nucleus transduction of FOXO3a. Besides, omentin1 also ameliorated unbalanced mitochondrial fusion-fission dynamics and activated mitophagy, thereby, improving the damaged mitochondria morphology and controlling mitochondrial quality in OGD-injured cardiomyocytes. Interestingly, SIRT3 played an important role in the improvement effects of omentin1 on mitochondrial function, unbalanced mitochondrial fusion-fission dynamics and mitophagy. Conclusion Omentin1 improves MI-induced HF and myocardial injury by maintaining mitochondrial dynamical homeostasis and activating mitophagy via upregulation of SIRT3/FOXO3a signaling. This study provides evidence for further application of omentin1 in cardiovascular diseases from the perspective of crosstalk between heart and adipose tissue.

Mitochondrial Dysfunction and Therapeutic Perspectives in Cardiovascular Diseases

“…In contrast, in BMAL1 deficient hESC-derived cardiomyocytes, impaired mitophagy is a key cause for the development of dilated cardiomyopathy [60]. In Hu's study, constructing mice with overexpression of omentin1 demonstrated that omentin1 activated mitophagy to improve HF [61]. In cardiac ischemia-reperfusion injury associated with disturbed mitochondrial homeostasis, the casein kinase 2α amplifies cardiomyocyte death signals by inhibiting mitophagy [62].…”

Prmt6-Foxo3a Attenuates Apoptosis by Upregulating Parkin Expression in Intestinal Ischemia-Reperfusion Injury

“…Foxo3a is a transcription factor that essential for cell survival and stress response, which involved in various cellular processes, including apoptosis and mitochondrial dynamics (28). Emerging evidence have demonstrated that Parkin interact with Foxo3a to coordinate mitochondrial dynamics, enhance mitochondrial quality control, and suppress cell apoptosis (42,43). In this study, we found Foxo3a blinds to Parkin and regulates the expression of Parkin protein.…”

Visualization analysis of mitochondrial dynamics in heart failure based on bibliometrics: Trends, hotspots, and topics

“…This further promotes the release of cytochrome C and apoptotic factors, thereby mediating changes in mitochondrial dynamics and inducing myocardial cell apoptosis. [23] Consequently, manipulating mitochondrial dynamics plays a crucial role in controlling…”