Sex-based differential regulation of oxidative stress in the vasculature by nitric oxide

• Published in: Redox biology Vol. 4; no. C; pp. 226 - 233
• Main Authors: Morales, Rommel C, Bahnson, Edward S M, Havelka, George E, Cantu-Medellin, Nadiezhda, Kelley, Eric E, Kibbe, Melina R
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier 01.04.2015
• Subjects: Animals; Carotid Arteries - cytology; Carotid Arteries - drug effects; Carotid Arteries - metabolism; Carotid Artery Injuries - genetics; Carotid Artery Injuries - metabolism; Carotid Artery Injuries - pathology; Cell Proliferation - drug effects; Endothelium, Vascular - drug effects; Endothelium, Vascular - metabolism; Endothelium, Vascular - pathology; Female; Gene Expression Regulation; Male; Myocytes, Smooth Muscle - drug effects; Myocytes, Smooth Muscle - metabolism; Myocytes, Smooth Muscle - pathology; Neointimal hyperplasia; Nitric oxide; Nitric Oxide - metabolism; Nitric Oxide - pharmacology; Nitric Oxide Donors - metabolism; Nitric Oxide Donors - pharmacology; Oxidative Stress - drug effects; Primary Cell Culture; Rats; Rats, Sprague-Dawley; Review; Sex differences; Sex Factors; Superoxide; Superoxide Dismutase - genetics; Superoxide Dismutase - metabolism; Superoxide Dismutase-1; Superoxides - metabolism; Vascular; Sex differences; Superoxide; Vascular; Neointimal hyperplasia; Nitric oxide
• ISSN: 2213-2317; 2213-2317
• DOI: 10.1016/j.redox.2015.01.007

Nitric oxide ((•)NO) is more effective at inhibiting neointimal hyperplasia following arterial injury in male versus female rodents, though the etiology is unclear. Given that superoxide (O2(•-)) regulates cellular proliferation, and (•)NO regulates superoxide dismutase-1 (SOD-1) in the vasculature, we hypothesized that (•)NO differentially regulates SOD-1 based on sex. Male and female vascular smooth muscle cells (VSMC) were harvested from the aortae of Sprague-Dawley rats. O2(•-) levels were quantified by electron paramagnetic resonance (EPR) and HPLC. sod-1 gene expression was assayed by qPCR. SOD-1, SOD-2, and catalase protein levels were detected by Western blot. SOD-1 activity was measured via colorimetric assay. The rat carotid artery injury model was performed on Sprague-Dawley rats ±(•)NO treatment and SOD-1 protein levels were examined by Western blot. In vitro, male VSMC have higher O2(•-) levels and lower SOD - 1 activity at baseline compared to female VSMC (P < 0.05). (•)NO decreased O2(•-) levels and increased SOD - 1 activity in male (P<0.05) but not female VSMC. (•)NO also increased sod- 1 gene expression and SOD - 1 protein levels in male (P<0.05) but not female VSMC. In vivo, SOD-1 levels were 3.7-fold higher in female versus male carotid arteries at baseline. After injury, SOD-1 levels decreased in both sexes, but (•)NO increased SOD-1 levels 3-fold above controls in males, but returned to baseline in females. Our results provide evidence that regulation of the redox environment at baseline and following exposure to (•)NO is sex-dependent in the vasculature. These data suggest that sex-based differential redox regulation may be one mechanism by which (•)NO is more effective at inhibiting neointimal hyperplasia in male versus female rodents.