Protection against cardiac hypertrophy by geniposide involves the GLP-1 receptor/AMPKα signalling pathway

Background and PurposeActivation of glucagon-like peptide-1 (GLP-1) receptor exerts a range of cardioprotective effects. Geniposide is an agonist of GLP-1 receptor, but its role in cardiac hypertrophy remains completely unknown. Here, we have investigated its protective effects and clarified the underlying molecular mechanisms. Experimental ApproachThe transverse aorta was constricted in C57/B6 mice and then geniposide was given orally for 7weeks. Morphological changes, echocardiographic parameters, histological analyses and hypertrophic markers were used to evaluate hypertrophy. Key ResultsGeniposide inhibited the hypertrophic response induced by constriction of the transverse aorta or by isoprenaline. Activation of 5-AMP-activated protein kinase- (AMPK) and inhibition of mammalian target of rapamycin, ERK and endoplasmic reticulum stress were observed in hypertrophic hearts that were treated with geniposide. Furthermore, Compound C (CpC) or knock-down of AMPK restricted protection of geniposide against cell hypertrophy and activation of mammalian target of rapamycin and ERK induced by hypertrophic stimuli. CpC or shAMPK also abolished the protection of geniposide against endoplasmic reticulum stress induced by thapsigargin or dihtiothreitol. The cardio-protective effects of geniposide were ablated in mice subjected to CpC. GLP-1receptor blockade counteracted the anti-hypertrophic response and activation of AMPK by geniposide. Knock-down of GLP-1 receptor also offset the inhibitory effects of geniposide on cardiac hypertrophy in vivo. Conclusions and ImplicationsGeniposide protected against cardiac hypertrophy via activation of the GLP-1 receptor/AMPK pathway. Geniposide is a potential therapeutic drug for cardiac hypertrophy.