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

Abstract

BackgroundMetabolic disorders such as obesity, insulin resistance and type 2 diabetes mellitus (DM2) are all linked to diabetic cardiomyopathy that lead to heart failure. Cardiomyopathy is initially characterized by cardiomyocyte hypertrophy, followed by mitochondrial dysfunction and fibrosis, both of which are aggravated by angiotensin. Caloric restriction (CR) is cardioprotective in animal models of heart disease through its catabolic activity and activation of the expression of adaptive genes. We hypothesized that in the diabetic heart; this effect involves antioxidant defenses and is mediated by SIRT1 and the transcriptional coactivator PGC-1α (Peroxisome proliferator-activated receptor-γ coactivator).MethodsObese Leptin resistant (db/db) mice characterized by DM2 were treated with angiotensin II (AT) for 4 weeks to enhance the development of cardiomyopathy. Mice were concomitantly either on a CR diet or fed ad libitum. Cardiomyocytes were exposed to high levels of glucose and were treated with EX-527 (SIRT1 inhibitor). Cardiac structure and function, gene and protein expression and oxidative stress parameters were analyzed.ResultsAT treated db/db mice developed cardiomyopathy manifested by elevated levels of serum glucose, cholesterol and cardiac hypertrophy. Leukocyte infiltration, fibrosis and an increase in an inflammatory marker (TNFα) and natriuretic peptides (ANP, BNP) gene expression were also observed. Oxidative stress was manifested by low SOD and PGC-1α levels and an increase in ROS and MDA. DM2 resulted in ERK1/2 activation. CR attenuated all these deleterious perturbations and prevented the development of cardiomyopathy. ERK1/2 phosphorylation was reduced in CR mice (p = 0.008). Concomitantly CR prevented the reduction in SIRT activity and PGC-1α (p < 0.04). Inhibition of SIRT1 activity in cardiomyocytes led to a marked reduction in both SIRT1 and PGC-1α. ROS levels were significantly (p < 0.03) increased by glucose and SIRT1 inhibition.ConclusionIn the current study we present evidence of the cardioprotective effects of CR operating through SIRT1 and PGC-1 α, thereby decreasing oxidative stress, fibrosis and inflammation. Our results suggest that increasing SIRT1 and PGC-1α levels offer new therapeutic approaches for the protection of the diabetic heart.

Weight loss enhances cardiac energy metabolism and function in heart failure associated with obesity

“…Seventh, weight loss improves cardiac ATP production in obese failing hearts, mainly through enhancing the contribution of glucose oxidation to ATP production. Taken together, our results show that weight loss dramatically improves cardiac function, remodelling and energy metabolism in obese mice with heart failure, which is in line with the cardiovascular benefits of caloric restriction . They also suggest that weight loss does not adversely affect heart failure severity, as would be suggested by the “obesity paradox”.…”

“…Despite the concept of the obesity paradox, it has been reported that weight loss can have beneficial cardiovascular effects in the setting of heart failure associated with obesity in humans and in animal models . Caloric restriction (CR) is one of the effective approaches to reduce body fat and improve glycaemic control, insulin sensitivity and lipid profiles . CR has also been shown to have a positive effect on blood pressure control in humans and to protect against diastolic dysfunction and adverse remodelling in experimental models of myocardial ischaemia/reperfusion injury, diabetic cardiomyopathy and heart failure .…”

“…18,19 Caloric restriction (CR) is one of the effective approaches to reduce body fat and improve glycaemic control, insulin sensitivity and lipid profiles. 18,20,21 CR has also been shown to have a positive effect on blood pressure control in humans 22 and to protect against diastolic dysfunction and adverse remodelling in experimental models of myocardial ischaemia/reperfusion injury, 23,24 diabetic cardiomyopathy 18,20 and heart failure. 19 Interestingly, caloric restrictioninduced cardioprotection has been suggested to be mediated through an age-independent manner.…”

Altered mitochondrial metabolism in the insulin‐resistant heart

“…In the hearts of fructose‐fed rats, Sirt1 activity decreased early in the progression to T2DM and was also associated with decreased in mitochondrial content and lower FAO capacity in the mitochondria . Recent evidence suggests that the cardioprotective effect of CR in the diabetic heart operates via Sirt1 and PGC‐1α, increasing OXPHOS capacity and reducing cardiomyocyte oxidative stress and inflammation . Caloric restriction was also associated with an increase in Sirt3 activity in cardiac mitochondria, without changes in expression level .…”

“…106 Recent evidence suggests that the cardioprotective effect of CR in the diabetic heart operates via Sirt1 and PGC-1α, increasing OXPHOS capacity and reducing cardiomyocyte oxidative stress and inflammation. 190 Caloric restriction was also associated with an increase in Sirt3 activity in cardiac mitochondria, 191 without changes in expression level. 192 The change in Sirt3 activity might be mediated via changes in the NAD + /NADH ratio, which decreases as a result of over-nutrition associated with obesity and T2DM (causing Sirt3 inactivation), and is increased by CR (causing Sirt3 activation).…”