Abstract 279: Vascular Aging In Aldosterone Associated Hypertension: Role Of NADPH Oxidase 1
In hypertension, vascular aging is accelerated leading to heart failure, stroke and renal dysfunction. Cellular and molecular mechanisms of age-associated vascular changes are unclear, but enhanced ROS generation by NADPH oxidases (Nox) and aldosterone (aldo) have been suggested. Nox1 is of particular interest due to increased levels in hypertension. Here, we postulated that aldo plays an important role in vascular aging through Nox1-dependent mechanisms. We examined signalling molecules associated with aging in arteries from 2 experimental models: stroke-prone spontaneously hypertensive rats (SHRSP) rats and Nox1 knockout mice infused with aldo (300 ug/Kg/day). Gene expression was assessed by qPCR and protein levels by immunoblotting. Aldo was measured by ELISA. In SHRSP rats, aging-associated mRNA inflammatory markers, such as RANTES (5- fold), MCP-1 (6-fold) and IL-6 (2-fold); as well as aldo levels (6-fold) and H2AX (marker of aging-associated DNA damage - 1.5-fold) were increased compared with control rats, p<0.05. In mice treated with aldo, JNK (pro-inflammatory - 69%) and p66SHC (pro-senescence - 92%) activation were increased in mesenteric arteries (p<0.05); an effect blunted in vessels from Nox1 KO mice. In parallel studies, vascular smooth muscle cells (VSMCs) from adult and aged control mice, as well as, from adult Nox1 transgenic mice (Nox1 overexpression in VSMCs) were extracted and stimulated with H2O2 and aldo. Basal levels of p66SHC (39%) and OGG-1 (48%), markers of senescence, were increased in VSMCs from aged animals, p<0.05. H2O2 (64%) and aldo (84%) increased p66SHC activation in VSMCs from adult mice to similar levels observed in cells from aged animals (p<0.05). However, aldo effects on p66SHC activation were exacerbated in VSMCs from adult Nox1 transgenic mice. In conclusion, aldosterone may play an important role in the aging-like phenotype in vascular injury associated with hypertension. Such processes may involve Nox1 and redox-sensitive p66Shc signalling.
Author Disclosures: A. Harvey: None. A. Montezano: None. D. Graham: None. Y. He: None. G. Ceravolo: None. C. Yabe-Nishimura: None. K. Griendling: None. R. Touyz: None.
- © 2014 by American Heart Association, Inc.