Lansoprazole Alleviates Pressure Overload-induced Cardiac Hypertrophy And Heart Failure In Mice By Blocking The Activation Of ?-catenin

Background and purpose:proton pump inhibitors(PPIs)are widely used in patients receiving percutaneous coronary intervention to prevent gastric bleeding,but whether PPIs are beneficial for the heart is controversial.Here we investigated the effects of lansoprazole on cardiac hypertrophy and heart failure,as well as the underlying mechanisms.Experimental approach:adult male C57 mice were subjected to transverse aortic constriction(TAC)or sham surgery and then were treated with lansoprazole or vehicle for 5 weeks.In addition,cultured neonatal rat ventricular cardiomyocytes and fibroblasts were exposed to angiotensin ? in the presence or absence of lansoprazole.Key results:at 5 weeks after TAC,the heart weight/body weight ratio was lower in lansoprazole-treated mice than in untreated mice(7.8±0.30 vs.9.1 ±0.47 mg/g),as was the lung weight/body weight ratio(14.9±1.09 vs.19.0±1.25 mg/g),while left ventricular fractional shortening and the maximum and minimum rates of change of the left ventricular pressure were higher in lansoprazole-treated mice,along with less cardiac fibrosis and lower expression of genes encoding atrial natriuretic peptide and myosin heavy chain ?.In cultured ventricular cardiomyocytes,lansoprazole inhibited angiotensin ?-induced protein synthesis and hypertrophy,as well as inhibiting proliferation of cultured ventricular fibroblasts.Myocardial expression of the proton pump H+/K+ATPase gene and protein were upregulated after TAC,while lansoprazole decreased myocardial levels of phosphorylated Akt,phosphorylated glycogen synthase kinase 3?,and active ?-catenin in TAC mice and in angiotensin ?-stimulated ventricular cardiomyocytes.Conclusions and implications:lansoprazole inhibits cardiac remodeling by suppressing activation of the Akt/GSK3?/?-catenin pathway,and these findings may provide a novel insight into the pharmacological effects of PPIs with regard to alleviation of cardiac remodeling.