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Nyui, N, Tamura, K, Mizuno, K, Ishigami, T, Hibi, K, Yabana, M, Kihara, M, Fukamizu, A, Ochiai, H, Umemura, S, Murakami, K, Ohno, S and Ishii, M (1997) Stretch-induced MAP kinase activation in cardiomyocytes of angiotensinogen-deficient mice. Biochem. Biophys. Res. Commun. 235:36-41
The renin-angiotensin system plays an important role in the hypertrophic responses in cardiac myocytes through the activation of signal transduction pathways and expression of oncogenes. In the present study, we examined mechanical stretch-induced activation of mitogen-activated protein kinases (MAP kinases) using cultured cardiac myocytes derived from neonatal angiotensinogen gene deficient mice (Agt-/-) and neonatal wild type mice (Agt+/+). Within 2 minutes of being added to cardiac myocytes, angiotensin II activated MAP kinases and the response was completely blocked by pretreatment of the cardiac myocytes with CV-11974, a selective antagonist of angiotensin II type 1 receptors. Interestingly, mechanical stretch resulted in significantly greater activation of MAP kinases in Agt-/- cardiac myocytes than in Agt+/+ cardiac myocytes. CV-11974 failed to suppress the stretch-induced activation of MAP kinases in Agt-/- cardiac myocytes while it inhibited the activation in Agt+/+ cardiac myocytes. BQ123, an endothelin type A receptor antagonist, had no effect on stretch-induced activation of MAP kinases in cardiac myocytes from either mouse strain. These results suggest that cardiac RAS is important for stretch-induced MAP kinase activation in Agt+/+ cardiac myocytes; however, angiotensin II is not indispensable for mechanical stretch-induced activation of MAP kinases in Agt-/- cardiac myocytes.
Angiotensin II/pharmacology; Angiotensin Receptor Antagonists; Angiotensinogen/deficiency; Angiotensinogen/genetics; Angiotensinogen/physiology; Animals; Benzimidazoles/pharmacology; Blotting, Western; Calcium-Calmodulin-Dependent Protein Kinases/metabolism; Cells, Cultured; Endothelin-1/pharmacology; Enzyme Activation; Gene Targeting; Mice; Mice, Transgenic; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Mitogen-Activated Protein Kinases; Myocardium/cytology; Myocardium/enzymology; Myocardium/metabolism; Peptides, Cyclic/pharmacology; Receptors, Endothelin/antagonists & inhibitors; Renin-Angiotensin System/physiology; Tetrazoles/pharmacology
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