Angiotensin II Type 2 Receptor Gene Transfer Downregulates Angiotensin II Type 1a Receptor in Vascular Smooth Muscle Cells

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Abstract
Two distinct subtypes of angiotensin (Ang) II receptors, type 1 (AT 1 ) and type 2 (AT 2 ), have been identified. Vascular smooth muscle cells (VSMCs) usually express AT 1 receptor. To elucidate the direct effects of the AT 2 receptor on the AT 1 receptor in VSMCs, we transfected AT 2 receptor gene into cultured rat VSMCs. Overexpression of AT 2 receptor significantly decreased expression of AT 1a receptor at both the mRNA and protein levels in the presence and absence of Ang II in VSMCs. Overexpression of AT 2 receptor increased expression of bradykinin and inducible NO in the presence and absence of Ang II in VSMCs. Bradykinin B 2 receptor antagonist HOE–140 and NO synthase inhibitor N ω -nitro- l -arginine methyl ester (L-NAME) inhibited the decreases in AT 1a receptor expression by the overexpression of AT 2 receptor in VSMCs. l -Arginine augmented the decrease in AT 1a receptor expression. Overexpression of AT 2 receptor suppressed basal DNA synthesis and proliferation of VSMCs and abolished response of DNA synthesis to Ang II in VSMCs. Our results demonstrate that overexpression of the AT 2 receptor downregulates AT 1a receptor expression in rat VSMCs in a ligand-independent manner that is mediated by the bradykinin/NO pathway. Downregulation of AT 1a receptor is a novel mechanism by which the AT 2 receptor regulates growth and metabolism of VSMCs.

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