[Molecular mechanism of cardiac hypertrophy and dysfunction]

We examined the signal transduction pathway for the development of cardiac hypertrophy induced by high blood pressure. The activities of Raf-1 kinase (Raf-1), mitogen-activated protein kinase kinase (MAPKK), MAP kinases (MAPKs) and 90-kDa ribosomal S6 kinase (p90rsk) was examined by passively stretching neonatal rat cardiomyocytes in vitro. Mechanical stretch activated these protein kinases transiently and sequentially: the maximal activation of Raf-1, MAPKK, MAPKs and p90rsk was observed at 2 minutes, 5 minutes, 8 minutes and 10 approximately 30 minutes, respectively. Both angiotensin II (AngII) and endothelin-1 (ET-1) were constitutively secreted from cultured cardiomyocytes, and a significant increase in the concentration was recognized in the culture medium of cardiomyocytes within 10 minutes after stretch. ET-1 mRNA levels were also increased in cardiomyocytes at 30 minutes after stretch. Moreover, ET-1 and AngII synergistically activated Raf-1 and MAPKs in cultured cardiomyocytes. In conclusion, mechanical stretch stimulates secretion and production of AngII and ET-1 in cultured cardiomyocytes, and both vasoconstrictive peptides may play an important role in mechanical stress (high blood pressure)-induced cardiac hypertrophy.