Differential Activation of Cardiac c-Jun Amino-Terminal Kinase and Extracellular Signal-Regulated Kinase in Angiotensin II–Mediated Hypertension

From the Department of Pharmacology, Osaka City University Medical School, (M.Y., S.K., Y.I., S.Y., H.I.), and Environmental Biological Life Science Research Center (BILIS), Inc (M.Y.), Shiga, Japan.

Correspondence to Shokei Kim, MD, Department of Pharmacology, Osaka City University Medical School, 1-4-54 Asahimachi, Abeno, Osaka 545-8585. Japan. E-mail kims{at}msic.med.osaka-cu.ac.jp

Abstract—Two subgroups of mitogen-activated protein kinases, c-jun NH₂-terminal kinase (JNK) and extracellular signal-regulated kinase (ERK), are thought to be involved in cultured cardiac myocyte hypertrophy and gene expression. To examine the in vivo activation of these kinases, we measured cardiac JNK and ERK activities in conscious rats subjected to acute or chronic angiotensin II (Ang II) infusion, by using in-gel kinase methods. About 50 mm Hg rise in blood pressure by Ang II (1000 ng · kg^-1 · min^-1) infusion caused larger activation of left ventricular JNK than ERK, via the AT₁ receptor. In spite of short duration (about 30 minutes) of maximal blood pressure elevation by Ang II, JNK sustained the peak value (more than 5-fold increase) from 15 minutes up to at least 3 hours. Similar activation of JNK was seen in the right ventricle. Thus, cardiac JNK activation by Ang II seems to be in part mediated by its direct action via the AT₁ receptor. The dose-response relationships for Ang II–induced rises in blood pressure and cardiac JNK and ERK activation indicated that cardiac JNK or ERK was not activated by a mild increase in blood pressure and that cardiac JNK was activated by Ang II–mediated hypertension in a more sensitive manner than ERK. Cardiac hypertrophy, induced by chronic Ang II infusion, was preceded by JNK activation without ERK activation. Furthermore, gel mobility shift analysis showed that cardiac JNK activation was followed by increased activator protein-1 DNA binding activity due to c-Fos and c-Jun. These results provided the first evidence for the preferential activation of cardiac JNK in Ang II–induced hypertension and suggested that JNK might play some role in Ang II–induced cardiac hypertrophic response in vivo. However, further study is needed to elucidate the role of JNK in cardiac hypertrophy in vivo.

Key Words: c-jun NH₂-terminal kinase • extracellular signal-regulated kinase • activator protein-1 • angiotensin II • cardiac hypertrophy

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