SIRT1 Activation by Resveratrol Alleviates Cardiac Dysfunction via Mitochondrial Regulation in Diabetic Cardiomyopathy Mice

Figure 3

Myocardial metabolic and mitochondrial alterations in DCM and SIRT1^KO mice. (a) TEM images revealed morphological mitochondrial impairment in both DCM and SIRT1^KO mice, and SIRT1 activation by resveratrol could alleviate these mitochondrial changes in DCM + RES mice. (b) Mitochondrial DNA (mtDNA) amount was significantly decreased in the DCM, SIRT1^KO, and SIRT1^KO + DCM groups as compared with the Con group (). Resveratrol elevated mtDNA amount in the DCM + R group (^#), while resveratrol’s protective effects were diminished in the SIRT1^KO + DCM + R group as compared with the DCM + RES group (^&). (c) Complex IV activity was significantly reduced in the DCM, SIRT1^KO, and SIRT1^KO + DCM groups () than in the Con group. Resveratrol markedly alleviated complex IV activity reduction in DCM mice (^#). While in contrast, the beneficial effect of resveratrol was completely abolished in the SIRT1^KO + DCM + R group (^&, SIRT1^KO + DCM + R versus DCM + RES). (d) Both DCM and SIRT1^KO led to defective ¹⁸F-FDG uptake in myocardium, and resveratrol ameliorated this in DCM + R mice but not in SIRT1^KO + DCM + R. (e) Insulin receptor substrate 2 (IRS2) protein level was reduced to about 60% in SIRT1^KO mouse hearts relative to WT mice, and impaired insulin signaling was revealed by reduced myocardial Akt phosphorylation in response to insulin stimulation (). In vitro insulin-induced phosphorylation of Akt at both T308 and S473 sites was also significantly diminished by SIRT1 sh-RNA (). versus Con; ^# versus DCM; ^& versus DCM + RES.

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