Angiotensin II (Ang II) is a potent vasopressor peptide that interacts with 2 major receptor isoforms -AT1 and AT2. Although blood pressure is increased in AT2 knockout mice, the underlying mechanisms remain undefined because of the low levels of expression of AT2 in the vasculature. Here we overexpressed AT2 in vascular smooth muscle (VSM) cells in transgenic (TG) mice. Aortic AT1 was not affected by overexpression of AT2. Chronic infusion of Ang II into AT2-TG mice completely abolished the AT1-mediated pressor effect, which was blocked by inhibitors of bradykinin type 2 receptor (icatibant) and nitric oxide (NO) synthase (L-NAME). Aortic explants from TG mice showed greatly increased cGMP production and diminished Ang II-induced vascular constriction. Removal of endothelium or treatment with icatibant and L-NAME abolished these AT2-mediated effects. AT2 blocked the amiloride-sensitive Na + /H + exchanger, promoting intracellular acidosis in VSM cells and activating kininogenases. The resulting enhancement of aortic kinin formation in TG mice was not affected by removal of endothelium. Our results suggest that AT2 in aortic VSM cells stimulates the production of bradykinin, which stimulates the NO/cGMP system in a paracrine manner to promote vasodilation. Selective stimulation of AT2 in the presence of AT1 antagonists is predicted to have a beneficial clinical effect in controlling blood pressure.
Background— Increased production of reactive oxygen species (ROSs) by angiotensin II (Ang II) is involved in the initiation and progression of cardiovascular diseases. NADPH oxidase is a major source of superoxide generated in vascular tissues. Although Nox1 has been identified in vascular smooth muscle cells as a new homolog of gp91phox (Nox2), a catalytic subunit of NADPH oxidase, the pathophysiological function of Nox1-derived ROSs has not been fully elucidated. To clarify the role of Nox1 in Ang II–mediated hypertension, we generated Nox1-deficient ( −/Y ) mice. Methods and Results— No difference in the baseline blood pressure was observed between Nox1 +/Y and Nox1 −/Y . Infusion of Ang II induced a significant increase in mean blood pressure, accompanied by augmented expression of Nox1 mRNA and superoxide production in the aorta of Nox1 +/Y , whereas the elevation in blood pressure and production of superoxide were significantly blunted in Nox1 −/Y . Conversely, the infusion of pressor as well as subpressor doses of Ang II did elicit marked hypertrophy in the thoracic aorta of Nox1 −/Y similar to Nox1 +/Y . Administration of a nitric oxide synthase inhibitor (L-NAME) to Nox1 +/Y did not affect the Ang II–mediated increase in blood pressure, but it abolished the suppressed pressor response to Ang II in Nox1 −/Y . Finally, endothelium-dependent relaxation and the level of cGMP in the isolated aorta were preserved in Nox1 −/Y infused with Ang II. Conclusions— A pivotal role for ROSs derived from Nox1/NADPH oxidase was suggested in the pressor response to Ang II by reducing the bioavailability of nitric oxide.
Objective. Interleukin-1 (IL-1) is a key cytokine linked to the pathogenesis of acute arthritis. Caspase 1, neutrophil elastase, and chymase all process proIL-1 to its biologically active form. This study was undertaken to examine the potential contributions of each of these proteases in experimental models of inflammatory arthritis.Methods. Conclusion. The production of IL-1 by neutrophils and mast cells is not exclusively dependent on caspase 1, and other proteases can compensate for the loss of caspase 1 in vivo. These pathways might therefore compromise the caspase 1-targeted therapies in neutrophil-predominant arthritis.
Recently, aldosterone has been shown to activate local renin-angiotensin system in vitro. To elucidate the potential role of local renin-angiotensin system in aldosterone-induced cardiovascular injury, we investigated the effects of selective mineralocorticoid receptor (MR) antagonist eplerenone (EPL), angiotensin (Ang) II type 1 receptor antagonist candesartan (ARB), and superoxide dismutase mimetic tempol (TEM) on the development of hypertension, vascular injury, oxidative stress, and inflammatory-related gene expression in aldosterone-treated hypertensive rats. The increased systolic blood pressure and vascular inflammatory changes were attenuated by cotreatment either with EPL, ARB, or TEM. Aldosterone increased angiotensin-converting enzyme expression in the aortic tissue; its effects were blocked by EPL but not by ARB or TEM. Aldosterone also increased Ang II contents in the aortic tissue in the presence of low circulating Ang II concentrations. Aldosterone induced expression of various inflammatory-related genes, whose effects were abolished by EPL, whereas the inhibitory effects of ARB and TEM varied depending on the gene. Aldosterone caused greater accumulation of the oxidant stress marker 4-hydroxy-2-neonenal in the endothelium; its effect was abolished by EPL, ARB, or TEM. Aldosterone increased mRNA levels of reduced nicotinamide adenine dinucleotide phosphate oxidase components; their effect was abolished by EPL, whereas ARB and TEM decreased only the p47phox mRNA level but not that of p22phox or gp91phox. The present findings suggest that the Ang II-dependent pathway resulting from vascular angiotensin-converting enzyme up-regulation and Ang II-independent pathway are both involved in the underlying mechanisms resulting in the development of hypertension, vascular inflammation, and oxidative stress induced by aldosterone.
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