Senolysis ameliorates increased susceptibility to ventricular arrhythmias in prediabetes

Abstract

Abstract Background Obesity and associated prediabetes are major risk factors for cardiovascular disease that promote cellular senescence and predispose to ventricular arrhythmias (VA). In consequence, targeting cellular senescence may represent a feasible therapeutical approach that can decrease VA susceptibility in aged hearts. The aim of the present study was to characterize the impact of senolysis on glucose control, left ventricular function (LVF) and VA susceptibility in a prediabetic mouse model. Methods Ten – 12 week-old C57Bl/6J mice were fed a high-fat diet over a period of 12 weeks to generate diet-induced-obesity (DIO). Afterwards, mice were treated with dasatinib (5 mg/kg) and quercetin (50 mg/kg) (DQ) or vehicle (10 % DMSO) by oral gavage three times in 7 days. Cardiac senescence was assessed by measuring Cdkn1a mRNA expression levels. Glucose control was monitored by glucose tolerance testing. LVF was evaluated by echocardiography and myocardial contractility was assessed by sarcomere length measurements in paced single cardiomyocytes. VA susceptibility testing was performed by programmed ventricle stimulation combined with an epicardial fluorescence imaging of the LV anterior wall in isolated hearts. VA susceptibility was quantified by an established scoring system. Results Cardiac senescence, as assessed by expression of Cdkn1a mRNA (encoding p21), was increased in DIO mice (P=0.0004, Figure 1A), whereas DQ reduced cardiac senescence (P<0.0001, Figure 1A). Glucose control was impaired in DIO mice (P<0.0001) and could be partially restored by DQ (P=0.003). LVF was ameliorated by DQ in DIO mice (P=0.018). In agreement, contractility in single cardiomyocytes was improved (Amplitude of sarcomere contraction: P=0.0003, figure 1B; speed of sarcomere contraction: P=0.046). VA susceptibility was increased in DIO mice (number of inducible VAs: P=0.001, figure 1C; VA score: P=0.0002; VT inducibility: P=0.001) whereas DQ limited VA susceptibility (number of induced VAs: P=0.004, Figure 1C; VA score: P=0.004; VT inducibility: P=0.025) in isolated hearts. Conclusions Our findings demonstrate that senolysis ameliorates glucose tolerance and LVF while reducing VA susceptibility in obesity and prediabetes. In consequence, senolysis may offer a perspective therapeutical approach for obese patients at risk for VAs. Further experiments will address underlying molecular mechanisms to identify potential therapeutical targets.