Search

Background: Cardiovascular ischemic events may occur more frequently in hypertensive patients with activated renin-angiotensin systems. We tested the hypothesis that angiotensin II (Ang II) may contribute to atherosclerosis by increasing expression of vascular inflammatory genes such as vascular cell adhesion molecule-1 (VCAM-1)., Methods and Results: Rats infused with norepinephrine or Ang II for 6 days developed similar hypertensive responses, but only Ang II-treated rats exhibited significant increases in aortic VCAM-1 protein and mRNA expression. Oral losartan treatment (50 mg. kg(-1). d(-1)) inhibited Ang II-induced hypertension and aortic VCAM-1 mRNA expression. Ang II treatment significantly increased VCAM-1 mRNA expression in cultured rat aortic smooth muscle cells (RASMCs). Ang II also induced nuclear NF-kappaB-like binding activity and transactivated an NF-kappaB-driven VCAM-1 promoter. Losartan and proteasome inhibitors blocked Ang II-induced NF-kappaB activation and VCAM-1 mRNA accumulation. IkappaB-alpha overexpression in RASMCs inhibited Ang II-induced VCAM-1 promoter transactivation., Conclusions: Ang II may contribute to atherogenesis by activation of VCAM-1 through proteasome dependent, NF-kappaB-like transcriptional mechanisms.

GRK5, a recently cloned member of the G protein-coupled receptor kinase family, has been shown to phosphorylate and participate in the desensitization of angiotensin II (Ang II) type 1A (AT1A) receptors. In this study, the effect of angiotensin II on GRK5 expression was examined in cultured vascular smooth muscle cells and aortas of Ang II-infused hypertensive rats. In vascular smooth muscle cells, Ang II (100 nM) up-regulated GRK5 mRNA as early as 1 h, with a peak at 16 h. This up-regulation was dose- and calcium-dependent. The increase in GRK5 mRNA was reflected in a smaller increase in protein expression, which nonetheless had functional significance since AT1 receptor phosphorylation was increased and phospholipase C activation was decreased following prolonged incubation with Ang II. In aortas of Ang II-infused hypertensive rats, both GRK5 mRNA and protein levels increased approximately 3-fold compared with sham-operated rats at 5 and 7 days, respectively. This up-regulation was blocked either by losartan or by the nonspecific vasodilator hydralazine. Since a subpressor dose of Ang II did not increase GRK5 mRNA levels and norepinephrine infusion also increased GRK5 mRNA expression, we conclude that Ang II-induced GRK5 up-regulation in rat aortas may be due to hypertension per se. Hormone- and hemodynamic stress-induced GRK5 regulation may provide a novel molecular basis for long-term regulation of agonist sensitivity of vascular cells.

Background: We investigated the in vivo effects of angiotensin (Ang) II-induced hypertension on heme oxygenase (HO) mRNA and protein expression, activity, and localization in rat aortas., Methods and Results: Infusion of Ang II (0.7 mg x kg(-1) x d(-1)) increased HO-1 mRNA levels to 169+/-31%, 251+/-47%, 339+/-26%, and 370+/-74% of the control level at 1, 3, 5, and 7 days after operation, respectively. The HO-1 protein level at 7 days was markedly upregulated, as was HO activity. Treatment with either losartan (25 mg x kg(-1) x d(-1)) or hydralazine (15 mg x kg(-1) x d(-1)), both of which prevented the Ang II-induced hypertension, blocked HO-1 mRNA upregulation. Norepinephrine infusion (2.8 mg x kg(-1) x d(-1)) produced a degree of hypertension and degree of HO-1 mRNA upregulation similar to those of Ang II infusion, which was again blocked by treatment with hydralazine (382+/-18% and 150+/-30% of the control level, respectively). Immunohistochemical analysis demonstrated that HO-1 is expressed in medial smooth muscle and adventitial cells in normotensive rat aortas, and this is markedly increased in adventitial and endothelial cells in Ang II-induced hypertensive rat aortas. In contrast, HO-2 protein expression was not changed in hypertensive rat aortas., Conclusions: These findings indicate that HO-1 is upregulated in hypertensive rat aortas, apparently by mechanisms unique to Ang II and by hemodynamic stress.

Experiments in cultured vascular smooth muscle cells have shown that angiotensin II (Ang II) stimulates expression of endothelin-1. We sought to examine role of endothelin-1 in the effects of Ang II in vivo. Ang II infusion in rats (0.7 mg/kg per day for 5 days) was associated with marked increases in vascular smooth muscle endothelin-1 levels, as assessed by immunostaining. Administration of the selective endothelin type A (ET(A)) receptor antagonist PD 155080 (50 mg/kg per day) abrogated the hypertensive response to a 5-day infusion of Ang II (0.7 mg/kg per day), as did losartan (25 mg/kg per day). ET(A) receptor blockade during Ang II-mediated hypertension was associated with marked elevations of plasma endothelin-1 levels. Ang II-mediated hypertension was associated with heightened vascular responsiveness to a variety of vasoconstrictor agents except endothelin-1. Blockade of ET(A) receptor invariably corrected this vasoconstrictor hyperresponsiveness. We conclude that some of the vascular effects of Ang II thought to be unique to this hormone are likely mediated by endothelin-1.

Background: The major source of superoxide (.O2-) in vascular tissues is an NADH/NADPH-dependent, membrane-bound oxidase. We have previously shown that this oxidase is activated in angiotensin II-but not norepinephrine-induced hypertension. We hypothesized that hypertension associated with chronically elevated angiotensin II might be caused in part by vascular .O2- production., Methods and Results: We produced hypertension in rats by a 5-day infusion of angiotensin II or norepinephrine. Rats were also treated with liposome-encapsulated superoxide dismutase (SOD) or empty liposomes. Arterial pressure was measured in conscious rats under baseline conditions and during bolus injections of either acetylcholine or nitroprusside. Vascular .O2- production was assessed by lucigenin chemiluminescence. In vitro vascular relaxations were examined in organ chambers. Norepinephrine infusion increased blood pressure to a similar extent as angiotensin II infusion (179 +/- 5 and 189 +/- 4 mm Hg, respectively). In contrast, angiotensin II-induced hypertension was associated with increased vascular .O2- production, whereas norepinephrine-induced hypertension was not. Treatment with liposome-encapsulated SOD reduced blood pressure by 50 mm Hg in angiotensin II-infused rats while having no effect on blood pressure in control rats or rats with norepinephrine-induced hypertension. Similarly, liposome-encapsulated SOD enhanced in vivo hypotensive responses to acetylcholine and in vitro responses to endothelium-dependent vasodilators in angiotensin II-treated rats., Conclusions: Hypertension caused by chronically elevated angiotensin II is mediated in part by .O2-, likely via degradation of endothelium-derived NO. Increased vascular .O2- may contribute to vascular disease in high renin/angiotensin II states.