Berberine alleviates myocardial diastolic dysfunction by modulating Drp1-mediated mitochondrial fission and Ca^(2+) homeostasis in a murine model of HFpEF

Heart failure with preserved ejection fraction(HFpEF)displays normal or near-normal left ventricular ejection fraction,diastolic dysfunction,cardiac hypertrophy,and poor exercise capacity.Berberine,an isoquinoline alkaloid,possesses cardiovascular benefits.Adult male mice were assigned to chow or high-fat diet with L-NAME(“two-hit”model)for 15 weeks.Diastolic function was assessed using echocardiography and noninvasive Doppler technique.Myocardial morphology,mitochondrial ultrastructure,and cardiomyocyte mechanical properties were evaluated.Proteomics analysis,autophagic flux,and intracellular Ca^(2+)were also assessed in chow and HFpEF mice.The results show exercise intolerance and cardiac diastolic dysfunction in“two-hit”-induced HFpEF model,in which unfavorable geometric changes such as increased cell size,interstitial fibrosis,and mitochondrial swelling occurred in the myocardium.Diastolic dysfunction was indicated by the elevated E value,mitral E/A ratio,and E/e’ratio,decreased e’value and maximal velocity of re-lengthening(-dL/dt),and prolonged re-lengthening in HFpEF mice.The effects of these processes were alleviated by berberine.Moreover,berberine ameliorated autophagic flux,alleviated Drp1 mitochondrial localization,mitochondrial Ca^(2+)overload and fragmentation,and promoted intracellular Ca^(2+)reuptake into sarcoplasmic reticulum by regulating phospholamban and SERCA2a.Finally,berberine alleviated diastolic dysfunction in“two-hit”diet-induced HFpEF model possibly because of the promotion of autophagic flux,inhibition of mitochondrial fragmentation,and cytosolic Ca^(2+)overload.