The Function And Mechanism Of Glucose-Regulated Protein 78 In Cardiac Hypertrophy

Background The heart manifests hypertrophic growth in response to elevation of afterload pressure.Cardiac myocyte growth involves new protein synthesis and membrane expansion,of which a number of cellular quality control machineries are stimulated to maintain function and homeostasis.The unfolded protein response(UPR)is potently induced during cardiac hypertrophy to enhance protein-folding capacity and eliminate terminally misfolded proteins.However,whether the UPR may directly enhance cardiac myocyte growth remains to be determined.Method In vivo experiments,a variety of genetically engineered mice,such as cardiac-specific GRP78 transgenic mice and cardiac-specific GRP78 conditional knockout mice,were used to stimulate cardiac atrophy in aortic coarctation,and body weight was evaluated by anatomical extraction.Cardiac weight,lung weight and tibia length were evaluated for cardiac hypertrophy and cardiopulmonary compensatory function.Cardiac H&E,WGA,Masson's and other pathological stains were used to evaluate myocardial cell cross-sectional area,myocardial fibrosis,echocardiographic detection of cardiac function,real-time fluorescence quantification.PCR to detect markers of cardiac remodeling and other methods to comprehensively evaluate the effect of GRP78 expression on cardiac structure and function.In vitro,the activation and utilization of downstream genes were detected by overexpressing exogenous GRP78 or interfering with the expression of endogenous GRP78 and luciferase reporter gene in primary cardiomyocytes isolated from neonatal SD rats.Immunofluorescence staining and radioisotope H3 labeled leucine uptake were used to assess changes in cardiomyocyte size.In addition,the interaction of GATA4 with GRP78 was detected by immunoblotting to elucidate the specific mechanism by which GRP78 affects cardiac hypertrophy.Results Here,we show that GRP78(glucose-regulated protein of 78 kDa),an endoplasmic reticulum resident protein chaperone,is augmented by cardiac hypertrophy.Importantly,overexpression of GRP78 in cardiomyocytes is sufficient to increase cell growth,which also potentiates hypertrophic stimulus-triggered growth response.At the in vivo level,transgenic hearts overexpressing GRP78 mount elevated hypertrophic growth in response to pressure overload.We went further to show that GRP78 increases the expression of GATA4,which may augment ANF level and promote cardiac hypertrophy.Silencing of GATA4 significantly diminishes GRP78-related growth response.Conclusions Our results therefore reveal that protein-folding chaperone GRP78 may directly enhance cardiac myocyte growth by stimulating cardiac-specific transcriptional factor GATA4.