Gender differences in superoxide generation in microvessels of hypertensive rats: role of NAD(P)H-oxidase.
OBJECTIVE
This study is aimed to explore whether gender plays a role in the generation of nitric oxide (NO) and superoxide anion (O(2)(-)) in microvessels of hypertensive rats (SHR), as well as the potential mechanisms involved in these effects.


RESULTS
NO generation in mesenteric arterioles was evaluated by measuring NO synthase (NOS) activity and protein expression. Oxidative stress was studied in vivo in mesenteric arterioles from male and female SHR by hydroethidine microfluorography. Although we did not observe any sex-related differences in NO generation, we found that hydroethitine oxidation is markedly increased (30.9+/-2.4%) in male compared to female (12.3+/-2.5%; p<0.05), demonstrating a gender difference in O(2)(-) production. The treatment of mesenteries with DPI (NAD(P)H-oxidase inhibitor) and treatment of SHR with losartan [Angiotensin-II type 1 (AT-1) receptor antagonist] markedly reduced O(2)(-) production in male, while produced a minor effect in female, suggesting that overexpression/activity of AT-1 receptor and NAD(P)H-oxidase contribute for the sexual dimorphism in superoxide generation. Immunoblot analyses provide evidences of overexpression of the NAD(P)H-oxidase components p22(phox), gp91(phox), p47(phox) and p67(phox) in arterioles from male in comparison to female. Losartan treatment inhibited the overexpression of these subunits in male, without affecting the responses in female.


CONCLUSIONS
Taken together, our findings demonstrate that male SHR presents higher superoxide anion concentration under basal condition than does female. An AT-1-dependent overexpression of the NAD(P)H-oxidase components may account for the sexual dimorphism in oxidative stress, and may play an important role in the noted gender differences on incidence of cardiovascular disease.
Dantas
Ana Paula V
AP
Laboratory of Hypertension, Department of Pharmacology, Institute of Biomedical Science, University of Sao Paulo, 05508-900, Av Prof Lineu Prestes, 1524, Room 217, Sao Paulo, SP, Brazil.
Franco
Maria do Carmo P
Mdo C
Silva-Antonialli
Michele M
MM
Tostes
Rita C A
RC
Fortes
Zuleica B
ZB
Nigro
Dorothy
D
Carvalho
Maria Helena C
MH
D000199:Actins / Q000378:metabolism; D000804:Angiotensin II / Q000378:metabolism; D000818:Animals; D001160:Arterioles; D004730:Endothelium, Vascular / Q000378:metabolism*; D005260:Female; D005783:Gender Identity; D006973:Hypertension / Q000378:metabolism*; D008297:Male; D008856:Microscopy, Fluorescence; D009247:NADH, NADPH Oxidoreductases / Q000502:physiology*; D019255:NADPH Oxidases; D009569:Nitric Oxide / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III; D051381:Rats; D011918:Rats, Inbred SHR; D013481:Superoxides / Q000378:metabolism*
D000199:Actins; D013481:Superoxides; D000804:Angiotensin II; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D052250:Nitric Oxide Synthase Type III; C496316:Nos3 protein, rat; D009247:NADH, NADPH Oxidoreductases; D019255:NADPH Oxidases