| Summary: | 博士 === 國立臺灣大學 === 動物科學技術學研究所 === 107 === According to the World Health Organization, heart diseases remained in the top rank of ten leading causes of death globally in the last 15 years. The heart is a highly oxidative tissue and mitochondria play a critical role in maintaining optimal cardiac function. Recently, mitochondrial dynamics have been connected with cardiovascular diseases (CVD). However, the exact role of mitochondrial dynamics in the pathogenesis of obesity cardiomyopathy (OCM) remains unclear. In present study, we established an OCM minipig model by high-fat diet (HFD) feeding for 6 months. These OCM pigs had a heavier body mass, accumulated more ectopic fat, and exhibited metabolic syndrome. The endoplasmic reticulum stress, autophagy, and lipotoxicity were participated in the cardiac pathological mechanism of OCM pigs. Moreover, a decreasing cardiac ATP production was observed in these OCM pigs. Therefore, the aim of this study was to elucidate the role of mitochondrial dynamics in OCM, in vitro and in vivo.
We found that enhanced cardiac oxidative stress, impairment of mitochondrial biogenesis and dynamics, and induced mitophagy were involved in the OCM pigs. To further elucidate the mechanisms of mitochondrial dynamics involved in HFD-induced cardiomyopathy, palmitate was used to induce lipotoxicity in H9C2 cells. In the cell model, palmitate disrupted mitochondrial dynamics and induced cell death, whereas inhibition of mitochondrial fission (DRP1) at the onset of lipotoxicity maintained the mitochondrial function and cell survival. However, there was lower basal mitochondrial oxidative function after prolonged palmitate treatment regardless of the functionality of siDRP1 was present or not. Meanwhile, there was more pericardial adipose tissue (PAT) accumulation around the heart. An elevated content of IL-6 and malondialdehyde was found in the PAT of obese pigs. To examine whether local effect of PAT secretomes regulated the mitochondrial function in OCM, H9C2 cells were treated with PAT-conditioned medium (CM). PAT-CM inhibited basal mitochondrial respiration and ATP production, thus leading to apoptosis of H9C2 cells. The protein expressions of mitochondrial dynamics- and a mitophagy-related protein were suppressed by PAT-CM.
In conclusion, the results indicated that mitochondrial dynamics was involved in the progression of HFD-induced cardiac pathogenesis. The model in vitro demonstrated that HFD caused cardiomyopathy via systemic effect (palmitate) and local regulation (PAT secretomes). Both palmitate and PAT secretomes disrupted mitochondrial functions and induced cell death, whereas inhibiting excessive mitochondrial fission at the onset of lipotoxicity provided a prolonged survival advantage, but did not restore mitochondrial function after prolonged lipotoxicity by palmitate. Despite the limitation, we showed a critical stage for potential new therapeutic strategies to reduce the risk of OCM via siDRP1.
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