The development of cardiac hypertrophy in response to increased hemodynamic load and neurohormonal stress is initially a compensatory response that may eventually lead to ventricular dilation and heart failure. Regulator of G protein signaling 5 (Rgs5) is a negative regulator of G protein-mediated signaling by inactivating Gα(q) and Gα(i), which mediate actions of most known vasoconstrictors. Previous studies have demonstrated that Rgs5 expresses among various cell types within mature heart and showed high levels of Rgs5 mRNA in monkey and human heart tissue by Northern blot analysis. However, the critical role of Rgs5 on cardiac remodeling remains unclear. To specifically determine the role of Rgs5 in pathological cardiac remodeling, we used transgenic mice with cardiac-specific overexpression of human Rgs5 gene and Rgs5 −/− mice. Our results demonstrated that the transgenic mice were resistant to cardiac hypertrophy and fibrosis through inhibition of MEK-ERK1/2 signaling, whereas the Rgs5 −/− mice displayed the opposite phenotype in response to pressure overload. These studies indicate that Rgs5 protein is a crucial component of the signaling pathway involved in cardiac remodeling and heart failure.
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...
Puerarin may have an ability to retard the progression of cardiac hypertrophy and apoptosis which is probably mediated by the blockade of PI3K/Akt and JNK signaling pathways.
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