(Hypertension. 2000;36:511.)
© 2000 American Heart Association, Inc.
Scientific Contributions |
Important Role of Angiotensin II–Mediated c-Jun NH2-Terminal Kinase Activation in Cardiac Hypertrophy in Hypertensive Rats
From the Department of Pharmacology, Osaka City University Medical School, Osaka 545-8585, Japan.
Correspondence to Shokei Kim, MD, Department of Pharmacology, Osaka City University Medical School, 1-4-3 Asahimachi, Abeno, Osaka 545-8585, Japan. E-mail kims{at}med.osaka-cu.ac.jp
Abstract—In vitro studies on the role of the mitogen-activated protein (MAP) kinase family (extracellular signal-regulated kinase [ERK], c-Jun NH2-terminal kinase [JNK], and p38) in cardiac hypertrophic response have produced confusing and contradictory results. We examined the in vivo role of the angiotensin II type 1 (AT1) receptor in cardiac MAP kinase activities during both the onset and development of cardiac hypertrophy in stroke-prone spontaneously hypertensive rats (SHRSP). In both the acute and chronic phases of cardiac hypertrophy in SHRSP, cardiac JNK activities were significantly increased compared with those in normotensive rats, whereas there was no prominent increase in cardiac ERK or p38 activities in SHRSP. Losartan, an AT1 receptor antagonist, prevented the onset of cardiac hypertrophy and regressed the progression of cardiac hypertrophy in SHRSP, being accompanied by the reduction of JNK activity and activator protein-1 (AP-1) activity in SHRSP. However, in spite of the normalization of blood pressure, hydralazine did not prevent or regress cardiac hypertrophy and did not decrease JNK or AP-1 activity in SHRSP. Inversely, hydralazine significantly increased the cardiac ERK activity in SHRSP by enhancing its phosphorylation. In conclusion, we have obtained the first evidence that the AT1 receptor is involved in the enhanced cardiac JNK activity in both the onset and development of cardiac hypertrophy of hypertensive rats. We propose that JNK is involved in AT1 receptor–mediated cardiac hypertrophy in vivo, in part mediated by the activation of AP-1.
Key Words: protein kinases • hypertrophy • hypertension, experimental • angiotensin • rats
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