OS 02-01 ROLE OF ALDOSTERONE AND NADPH OXIDASE 1 IN HYPERTENSION-ASSOCIATED VASCULAR AGING.

OBJECTIVE: In hypertension, the vasculature undergoes alterations that resemble those seen in aging. The involvement of aldosterone and Noxs in the mechanisms underlying age-associated vascular damage is unclear. We postulated that aging-like changes in the vasculature is amplified in hypertension due to increased aldosterone-induced Nox-redox signalling.

DESIGN AND METHOD: We assessed vascular aging in arteries from adult WKY (18 weeks), aged WKY (52 weeks) and adult stroke-prone spontaneously hypertensive (SHRSP) rats. Vascular smooth muscle cells (VSMC) were also used. Blood pressure was measured by tail-cuff. Vascular function was analysed by wire myography and structure by pressure myography. Gene expression was assessed by qPCR and protein levels by immunoblotting. Plasma Gal-3, aldosterone and peroxynitrite were measured by ELISA.

RESULTS: BP was increased only in SHRSP rats. Vascular hypercontractility in aged WKY was similar to that in SHRSP rats and normalised by inhibition of Nox1. Plasma aldosterone levels were elevated in SHRSP (p < 0.05; vs. WKY) and eplerenone normalised hypercontractility only in SHRSP. Increased vascular stiffness and fibrosis were observed in arteries from SHRSP compared to adult WKY rats. mRNA expression of Nox2, NoxA1 and NoxO1 was increased (p < 0.05; vs. WKY), while Nox4, p22phox and p47 phox gene levels were unchanged, in vessels from aged WKY and SHRSP rats. Nox1 mRNA expression and increased peroxynitrite were only increased in SHRSP rats (p < 0.05; vs. WKY). Aldosterone-induced Nox1 mRNA expression was exaggerated in VSMCs from SHRSP rats. p66SHC, an important pro-aging molecule, was activated in SHRSP and aged WKY arteries. In VSMCs, p66shc activation by aldosterone was blocked by ML171 (Nox1 inhibitor) and blunted in the vasculature from Nox1 KO mice.

CONCLUSIONS: In conclusion, aging-like vascular phenotypes are associated with increased levels of Nox1 related genes and can be normalised by Nox1 inhibitors. Increased activation of Nox1 by aldosterone may contribute to an 'aging' vascular phenotype in hypertension.