Caloric restriction reduces sympathetic activity similar to beta-blockers but conveys additional mitochondrio-protective effects in aged myocardium

Abstract

Increased activation of sympathetic nervous system contributes to congestive heart failure (CHF) progression, and inhibition of sympathetic overactivation by beta-blockers is successful in CHF patients. Similarly, caloric restriction (CR) reduces sympathetic activity but mediates additional effects. Here, we compared the cardiac effects of CR (− 40% kcal, 3 months) with beta-blocker therapy (BB), diuretic medication (DF) or control diet in 18-months-old Wistar rats. We continuously recorded blood pressure, heart rate, body temperature and activity with telemetric devices and analysed cardiac function, activated signalling cascades and markers of apoptosis and mitochondrial biogenesis. During our study, left ventricular (LV) systolic function improved markedly (CR), mildly (BB) or even deteriorated (DF; control). Diastolic function was preserved by CR and BB but impaired by DF. CR reduced blood pressure identical to DF and BB and heart rate identical to BB. Plasma noradrenaline was decreased by CR and BB but increased by DF. Only CR reduced LV oxidative damage and apoptosis, induced AMPK and Akt phosphorylation and increased mitochondrial biogenesis. Thus, additive to the reduction of sympathetic activity, CR achieves protective effects on mitochondria and improves LV function and ROS damage in aged hearts. CR mechanisms may provide additional therapeutic targets compared to traditional CHF therapy.

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“…Studies in experimental animals back up this finding by showing that caloric restriction decreases tumor formation and slows tumor growth (reviewed in Lv et al [ 152 ]. For instance, caloric restriction reduces sympathetic activity to an extent comparable to beta-blockers in rodents [ 174 ]. Thus, weight loss represents a good intervention measure for the prevention of several human cancers, including HCC, PDAC, and breast cancer.…”

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“…Despite diverging therapeutic indications -belzutifan for Von Hippel-Lindau (VHL) syndrome-associated clear-cell renal cell carcinoma (ccRCC), carvedilol for hypertension, and daclatasvir for Chronic hepatitis C genotype 3 (GT-3 HCV) -their MOAs suggest that they may exert similar effects on cardiomyocytes. Belzutifan inhibits hypoxia-inducible factor 2α (HIF-2α), and research suggests that HIF-2α inhibitors can reverse pulmonary hypertension and that there are shared pathophysiologic mechanisms between cancer and heart failure 40,41 . Carvedilol, a nonselective betaadrenergic antagonist, has anti-free radical and antioxidant effects, and can resist oxidation and reduce ROS production 42 .…”

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“…To better understand the results presented in Belzutifan inhibits hypoxia-inducible factor 2α (HIF-2α), and research suggests that HIF-2α inhibitors can reverse pulmonary hypertension and that there are shared pathophysiologic mechanisms between cancer and heart failure [24,25] . Carvedilol, a nonselective beta-adrenergic antagonist, has anti-free radical and antioxidant effects, and can resist oxidation and reduce ROS production [26] . It also inhibits the Cardiac Mitochondrial Permeability Transition (MPT), which can depolarize mitochondrial membranes and uncouple oxidative phosphorylation (OXPHOS) [27] .…”