The AngII type 1 receptor antagonist TCV116 reduced left ventricular hypertrophy and fibrosis in vivo, while mechanical stretch activated MAP kinase pathways differently across cardiac cell types.
Mechanical stretch induces cardiac hypertrophy via specific molecular pathways including MAP kinase activation, which differs between cardiomyocytes and fibroblasts, and is attenuated by AngII type 1 receptor antagonism.
Mechanical stretch induced by high blood pressure is an initial factor leading to cardiac hypertrophy. In an in vivo study, an angiotensin II (AngII) type 1 receptor antagonist TCV116 reduced left ventricular (LV) weight, LV wall thickness, transverse myocyte diameter, relative amount of V3 myosin heavy chain, and interstitial fibrosis, while treatment with hydralazine did not. In an in vitro study using cultured cardiomyocytes, mechanical stretch activated second messengers such as mitogen-activated protein (MAP) kinase, followed by increased protein synthesis. Additionally, in the stretch-conditioned medium AngII and endothelin-1 concentrations were increased. Furthermore, the Na+/H+ exchanger activated by mechanical stretch modulated the hypertrophic responses of cardiomyocytes. The pathways leading to MAP kinase activation differed between cell types. In cardiac fibroblasts AngII activated MAP kinase via G beta gamma subunit of Gi, Src, Shc, Grb2, and Ras, whereas Gq and protein kinase C were critical in cardiomyocytes.
Yamazaki et al. (Tue,) conducted a other in Cardiac hypertrophy and failure. TCV116 (AngII type 1 receptor antagonist) vs. Hydralazine was evaluated on Left ventricular weight, wall thickness, myocyte diameter, V3 myosin heavy chain, and interstitial fibrosis. The AngII type 1 receptor antagonist TCV116 reduced left ventricular hypertrophy and fibrosis in vivo, while mechanical stretch activated MAP kinase pathways differently across cardiac cell types.
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