Molecular basis of cardiac hypertrophy.
Cardiac hypertrophy is an adaptive process to an increased hemodynamic overload. When cardiomyocytes cultured on silicone dishes were stretched, second messengers such as protein kinase C (PKC), Raf-1 kinase, and mitogen-activated protein (MAP) kinases were activated, which were followed by increased protein synthesis. Moreover, pretreatment with an angiotensin II (AngII) type 1 receptor antagonist dimished an increase in protein synthesis, MAP kinase activity, and c-fos gene expression induced by the stretching of cardiomyocytes. These suggest the linkage of the cardiac renin-angiotensin system to the formation of pressure-overload hypertrophy. Indeed, in the stretch-conditioned medium the levels of AngII concentration were increased. Also, mechanical stretch enhanced endothelin (ET)-1 release from the cardiomyocytes and activated the Na(+)/H(+) exchanger independently of these vasoactive peptides. In the second part, we examined AngII-induced signaling pathways both in cardiac myocytes and in cardiac fibroblasts. AngII-evoked signal transduction pathways differed between cell types. In cardiac fibroblasts AngII activated MAP kinases through a pathway including the Gbetagamma subunit of Gi protein, Src, Shc, Grb2, and Ras, while Gq and PKC activation was necessary in cardiac myocytes. We further explored norepinephrine (NE)-induced signaling pathways in cardiac myocytes. NE activated Raf-1 kinase and MAP kinases and increased amino acid uptake in cardiomyocytes of neonatal rats. beta-adrenoceptor (AR) stimulation as well and alpha1-AR stimulation was involved in NE-induced MAP kinase activation. It is noteworthy that unlike in other cell types not only PKC activation but also protein kinase A (PKA) activation increased the activities of Raf-1 kinase and MAP kinases in cardiac myocytes and induced cell growth. Finally, we observed that beta-AR-induced activation of MAP kinases is dependent on both Gs/cAMP/PKA and Gi/Src/Ras signaling pathways and that phosphorylation of beta-AR is critical to the cross talk between these signaling pathways.
Yamazaki
T
T
Department of Cardiovascular Medicine and Department of Pharmacoepidemiology, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655 Japan. yama-tky@umin.ac.jp
Yazaki
Y
Y
D000818:Animals; D006332:Cardiomegaly / Q000503:physiopathology*; D019332:Endothelin-1 / Q000502:physiology; D006439:Hemodynamics / Q000502:physiology; D006801:Humans; D020928:Mitogen-Activated Protein Kinases; D009206:Myocardium / Q000201:enzymology; D009638:Norepinephrine / Q000502:physiology; D011493:Protein Kinase C / Q000502:physiology; D019908:Proto-Oncogene Proteins c-raf / Q000502:physiology; D051381:Rats; D011943:Receptors, Adrenergic, beta / Q000502:physiology; D012084:Renin-Angiotensin System / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology
D019332:Endothelin-1; D011943:Receptors, Adrenergic, beta; D019908:Proto-Oncogene Proteins c-raf; D011493:Protein Kinase C; D020928:Mitogen-Activated Protein Kinases; D009638:Norepinephrine