Rosmarinic acid ameliorated cardiac dysfunction and mitochondrial injury in diabetic cardiomyopathy mice via activation of the SIRT1/PGC-1α pathway.

Mitochondrial injury plays an essential role in the pathogenesis of diabetic cardiomyopathy (DCM). Previous studies demonstrated that rosmarinic acid (RA) treatment prevented high glucose-induced mitochondrial injury in vitro. However, whether RA can ameliorate cardiac function by preventing mitochondrial injury in DCM is unknown. The SIRT1/PGC-1α pathway has emerged as an important regulator of metabolic control and other mitochondrial functions. The present study was undertaken to determine the effects of RA on mitochondrial and cardiac function in DCM as well as the involvement of the SIRT1/PGC-1α pathway. Our results revealed that RA improved cardiac systolic and diastolic function and prevented mitochondrial injury in DCM, as shown by the reduced blood glucose and lipid levels, increased mitochondrial membrane potential levels, improved adenosine triphosphate synthesis, and inhibited apoptosis (P < 0.05). Moreover, RA upregulated the expression of SIRT1 and PGC-1α in DCM mice and high glucose-treated H9c2 cardiomyocytes (P < 0.05). Further mechanistic studies in H9c2 cardiomyocytes revealed that suppression of SIRT1 by Sh-SIRT1 counteracted the effects of RA on high glucose-induced abnormal metabolism of glucose and lipids, oxidative stress and apoptosis (P < 0.05). Taken together, these data indicate that RA prevented mitochondrial injury and cardiac dysfunction in DCM mice, and the SIRT1/PGC-1α pathway mediated the protective effects of RA.

Diao J ，Zhao H ，You P ，You H ，Wu H ，Shou X ，Cheng G ... -  《-》

The Role of Heme Oxygenase 1 in the Protective Effect of Caloric Restriction against Diabetic Cardiomyopathy.

Waldman M ，Nudelman V ，Shainberg A ，Zemel R ，Kornwoski R ，Aravot D ，Peterson SJ ，Arad M ，Hochhauser E ... -  《INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES》

Resveratrol alleviates diabetic cardiomyopathy in rats by improving mitochondrial function through PGC-1α deacetylation.

Fang WJ ，Wang CJ ，He Y ，Zhou YL ，Peng XD ，Liu SK ... -  《-》

Melatonin prevents Drp1-mediated mitochondrial fission in diabetic hearts through SIRT1-PGC1α pathway.

Myocardial contractile dysfunction is associated with an increase in mitochondrial fission in patients with diabetes. However, whether mitochondrial fission directly promotes diabetes-induced cardiac dysfunction is still unknown. Melatonin exerts a substantial influence on the regulation of mitochondrial fission/fusion. This study investigated whether melatonin protects against diabetes-induced cardiac dysfunction via regulation of mitochondrial fission/fusion and explored its underlying mechanisms. Here, we show that melatonin prevented diabetes-induced cardiac dysfunction by inhibiting dynamin-related protein 1 (Drp1)-mediated mitochondrial fission. Melatonin treatment decreased Drp1 expression, inhibited mitochondrial fragmentation, suppressed oxidative stress, reduced cardiomyocyte apoptosis, improved mitochondrial function and cardiac function in streptozotocin (STZ)-induced diabetic mice, but not in SIRT1-/- diabetic mice. In high glucose-exposed H9c2 cells, melatonin treatment increased the expression of SIRT1 and PGC-1α and inhibited Drp1-mediated mitochondrial fission and mitochondria-derived superoxide production. In contrast, SIRT1 or PGC-1α siRNA knockdown blunted the inhibitory effects of melatonin on Drp1 expression and mitochondrial fission. These data indicated that melatonin exerted its cardioprotective effects by reducing Drp1-mediated mitochondrial fission in a SIRT1/PGC-1α-dependent manner. Moreover, chromatin immunoprecipitation analysis revealed that PGC-1α directly regulated the expression of Drp1 by binding to its promoter. Inhibition of mitochondrial fission with Drp1 inhibitor mdivi-1 suppressed oxidative stress, alleviated mitochondrial dysfunction and cardiac dysfunction in diabetic mice. These findings show that melatonin attenuates the development of diabetes-induced cardiac dysfunction by preventing mitochondrial fission through SIRT1-PGC1α pathway, which negatively regulates the expression of Drp1 directly. Inhibition of mitochondrial fission may be a potential target for delaying cardiac complications in patients with diabetes.

Ding M ，Feng N ，Tang D ，Feng J ，Li Z ，Jia M ，Liu Z ，Gu X ，Wang Y ，Fu F ，Pei J ... -  《-》

Regulation of diabetic cardiomyopathy by caloric restriction is mediated by intracellular signaling pathways involving 'SIRT1 and PGC-1α'.

Waldman M ，Cohen K ，Yadin D ，Nudelman V ，Gorfil D ，Laniado-Schwartzman M ，Kornwoski R ，Aravot D ，Abraham NG ，Arad M ，Hochhauser E ... -  《Cardiovascular Diabetology》