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 7 weeks. 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-α (AMPKα) 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 AMPKα restricted protection of geniposide against cell hypertrophy and activation of mammalian target of rapamycin and ERK induced by hypertrophic stimuli. CpC or shAMPKα 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 AMPKα 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/AMPKα pathway. Geniposide is a potential therapeutic drug for cardiac hypertrophy. AbbreviationsAICAR, 5-aminoimidazole-4-carboxamide 1-β-D-ribofuranoside; AMPK, 5′-AMP-activated protein kinase; Ang, angiotensin; ANP, atrial natriuretic peptide; CpC, Compound C; CSA, cross-sectional area; Ex, Exendin; FS, fractional shortening; GE, geniposide; GLP, glucagon-like peptide; HW/BW, heart weight/body weight; HW/TL, heart weight/tibia length; LVIDd, left ventricular internal diastolic diameter; mTOR, mammalian target of rapamycin; TAC, constriction of the transverse aorta; TG, thapsigargin; β-MHC, β-myosin heavy chain IntroductionCardiac hypertrophy is characterized by enlargement of the heart and is the response of the heart to a variety of stimuli (Tang et al., 2009). It can progress to heart failure, and ultimately leads to high rates of mortality and morbidity (Shah and Mann, 2011). Although considerable progress has been made in understanding the molecular mechanisms underlying hypertrophy, drugs that constrain these pathways are yet to be discovered. One of the mechanisms that could promote cardiac hypertrophy is endoplasmic reticulum (ER) stress. Once ER stress is activated, branches of the protein response increase ROS and induce apotosis, contributing to the process of cardiac hypertrophy (McCullough et al., 2001;Harding et al., 2003). Therefore, it is of im...

Seedling emergence in monocots depends mainly on mesocotyl elongation, requiring the coordination between developmental signals and environmental stimuli. Strigolactones (SLs) and karrikins are butenolide compounds that regulate various developmental processes; both are able to negatively regulate rice (Oryza sativa) mesocotyl elongation in the dark. Here, we report that a karrikin signaling complex, DWARF 14-LIKE (D14L)-DWARF 3 (D3)-Oryza sativa SUPPRESSOR OF MAX2 1 (OsSMAX1) mediates the regulation of rice mesocotyl elongation in the dark. We demonstrate that D14L recognizes the karrikin signal and recruits

Mesenchymal cells expressing platelet-derived growth factor receptor beta (PDGFRβ) are known to be important in fibrosis of organs such as the liver and kidney. Here we show that PDGFRβ+ cells contribute to skeletal muscle and cardiac fibrosis via a mechanism that depends on αv integrins. Mice in which αv integrin is depleted in PDGFRβ+ cells are protected from cardiotoxin and laceration-induced skeletal muscle fibrosis and angiotensin II-induced cardiac fibrosis. In addition, a small-molecule inhibitor of αv integrins attenuates fibrosis, even when pre-established, in both skeletal and cardiac muscle, and improves skeletal muscle function. αv integrin blockade also reduces TGFβ activation in primary human skeletal muscle and cardiac PDGFRβ+ cells, suggesting that αv integrin inhibitors may be effective for the treatment and prevention of a broad range of muscle fibroses.

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