The study demonstrates a previously unrecognized role for AT2 receptors in the heart, specifically coupling angiotensin II to protein kinase C activation.
To define the signal transduction pathway linked to the cardiac angiotensin II (AII) receptor type 2 (AT2-R), cardiomyocytes were prepared as primary culture from 7-day-old chick embryo hearts. Protein kinase C (PKC) activity was assayed in membrane and cytosolic fractions of the cardiac cells. AII significantly (p < 0.05) increased membrane PKC activity and decreased cytosolic PKC activity, in a concentration-dependent manner, suggesting a translocation of PKC from cytosol to membrane. AT2-R blockade by its antagonist, PD123319, produced a dose-dependent antagonism of AII-induced activation of PKC. PD123319, at 10(-6) M or greater concentrations, completely antagonized AII-induced PKC activation, in contrast to a small reduction in PKC activity by the AII receptor type 1 (AT1-R) antagonist losartan. Isoproterenol-induced cAMP generation was significantly (p < 0.05) blunted by AII. AT2-R blockade did not alter AII-induced reduction of beta-adrenoceptor-mediated increases in cAMP generation, in contrast with AT1-R blockade, which abolished AII-induced reduction of beta-adrenergic-mediated cAMP production. These data suggest that AT2 receptors have a previously unrecognized, role in the heart, namely, coupling AII to PKC.
Simon W. Rabkin (Thu,) studied this question.
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