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Activation of Endothelial Nitric Oxide Synthase by the Angiotensin II Type 1 Receptor

Cardiovascular Research Center and Department of Physiology (H.S., K.E., H.O., S.H., S.D., S.E.), Temple University School of Medicine, Philadelphia, Pennsylvania 19140; Department of Biochemistry (G.D.F.), Vanderbilt University School of Medicine, Nashville, Tennessee 37232; and Department of Biomedical Sciences (E.D.M.), Meharry Medical College, Nashville, Tennessee 37208

Address all correspondence and requests for reprints to: Satoru Eguchi, M.D., Ph.D., FAHA, Cardiovascular Research Center and Department of Physiology, Temple University School of Medicine, 3420 North Broad Street, Philadelphia, Pennsylvania 19140. E-mail: seguchi{at}temple.edu.

Enhanced angiotensin II (AngII) action has been implicated in endothelial dysfunction that is characterized as decreased nitric oxide availability. Although endothelial cells have been reported to express AngII type 1 (AT₁) receptors, the exact role of AT₁ in regulating endothelial NO synthase (eNOS) activity remains unclear. We investigated the possible regulation of eNOS through AT₁ in bovine aortic endothelial cells (BAECs) and its functional significance in rat aortic vascular smooth muscle cells (VSMCs). In BAECs infected with adenovirus encoding AT₁ and in VSMCs infected with adenovirus encoding eNOS, AngII rapidly stimulated phosphorylation of eNOS at Ser¹¹⁷⁹. This was accompanied with increased cGMP production. These effects were blocked by an AT₁ antagonist. The cGMP production was abolished by a NOS inhibitor as well. To explore the importance of eNOS phosphorylation, VSMCs were also infected with adenovirus encoding S1179A-eNOS. AngII did not stimulate cGMP production in VSMCs expressing S1179A. However, S1179A was able to enhance basal NO production as confirmed with cGMP production and enhanced vasodilator-stimulated phosphoprotein phosphorylation. Interestingly, S1179A prevented the hypertrophic response similar to wild type in VSMCs. From these data, we conclude that the AngII/AT₁ system positively couples to eNOS via Ser¹¹⁷⁹ phosphorylation in ECs and VSMCs if eNOS and AT₁ coexist. However, basal level NO production may be sufficient for prevention of AngII-induced hypertrophy by eNOS expression. These data demonstrate a novel molecular mechanism of eNOS regulation and function and thus provide useful information for eNOS gene therapy under endothelial dysfunction.

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