Syndecan 4 Signaling Is Required For Exercise-Induced Cardiac Hypertrophy

BACKGROUND AND OBJECTCardiac hypertrophy can be broadly classified as either physiological or pathological.Physiological stimulus such as exercise cause adaptive cardiac hypertrophy and normal heart function.Pathological stimulus such as hypertension and aortic valvular stenosis cause maladaptive cardiac remodeling and ultimately heart failure.Syndecan 4(synd4)is a transmembrane proteoglycan and identified to be involved in cardiac adaptation after injury.Whether it takes part in physiological cardiac hypertrophy is unclear.METHODSImmunohistochemistry assay and western blot were performed to detect the expression of syndecan4 in exercise-induced hypertrophic myocardium.Synd4 knockout mice were exercised by swimming for 4 weeks,in Ultrasonic cardiogram(UCG)assay,IVSD?LVPWD?LVESD?LVEDD?FS?EF were used to compare cardiac structure and function between transgenic and WT mice.In histological assay,cardiac hypertrophy was assessed by measuring the ratio of heart weight to body weight(HW/BW)?the cardiomyocyte cross-sectional areas?the level of fibrosis and apoptosis in the ventricular wall.Adenovirus was employed to over-express syndecan4 in neonatal mice ventricular cardiomyocytes(NMCMs).Fetal gene expression,genes expression associated with contractile function,lipid metabolism related genes,glucose metabolism related genes,amino acid uptake rate and the cell size were analyzed to evaluate the hypertrophy of NMCMs.Akt signaling pathway was examined by western blot.Calphostin C,was used to inhibit protein kinase C(PKC),western blot and histological assay were performed to detected the synd4 induced hypertrophic phenotype and Akt phosphorylation.RESULTS:We observed up-regulation of synd4 in exercise-induced hypertrophic myocardium.To evaluate the role of synd4 in the physiological form of cardiac hypertrophy,mice lacking synd4(synd4-/-)were exercised by swimming for 4 weeks.UCG and histological analysis revealed that swimming-induced the hypertrophic phenotype was blunted in synd4-/-compared with WT mice.The swimming-induced activation of Akt,a key molecule in physiological hypertrophy was also decreased than that seen in wild-type controls.In cultured cardiomyocytes,synd4 expression could induce cell enlargement,protein synthesis,and distinct physiological molecular alternation.Akt activation was also observed in synd4 expressed cardiomyocytes.Furthermore inhibition of PKC prevented the synd4 induced hypertrophic phenotype and Akt phosphorylation.CONCLUSIONThis study identifies an essential role of synd4 in mediation of physiological cardiac hypertrophy.