Role of gp91^phox-containing NADPH oxidase in left ventricular remodeling induced by intermittent hypoxic stress

Abstract

Intermittent hypoxia due to sleep apnea syndrome is associated with cardiovascular diseases. However, the precise mechanisms by which intermittent hypoxic stress accelerates cardiovascular diseases are largely unclear. The aim of this study was to investigate the role of gp91(phox)-containing NADPH oxidase in the development of left ventricular (LV) remodeling induced by intermittent hypoxic stress in mice. Male gp91(phox)-deficient (gp91(-/-)) mice (n = 26) and wild-type (n = 39) mice at 7-12 wk of age were exposed to intermittent hypoxia (30 s of 4.5-5.5% O(2) followed by 30 s of 21% O(2) for 8 h/day during daytime) or normoxia for 10 days. Mean blood pressure and LV systolic and diastolic function were not changed by intermittent hypoxia in wild-type or gp91(-/-) mice, although right ventricular systolic pressure tended to be increased. In wild-type mice, intermittent hypoxic stress significantly increased the diameter of cardiomyocytes and interstitial fibrosis in LV myocardium. Furthermore, intermittent hypoxic stress increased superoxide production, 4-hydroxy-2-nonenal protein, TNF-alpha and transforming growth factor-beta mRNA, and NF-kappaB binding activity in wild-type, but not gp91(-/-), mice. These results suggest that gp91(phox)-containing NADPH oxidase plays a crucial role in the pathophysiology of intermittent hypoxia-induced LV remodeling through an increase of oxidative stress.

Pitavastatin reduces oxidative stress and attenuates intermittent hypoxia-induced left ventricular remodeling in lean mice

“…39,40 We also reported elevated interleukin-6, TNF-a mRNA and NF-kB-binding activity in the LV myocardium of mice exposed to intermittent hypoxia. 5,18 These results suggest that inflammatory cytokines might be involved in the LV remodeling induced by intermittent hypoxia. In this study, pitavaststin reduced the mRNA expression level of TNF-a in the LV myocardium, thereby preventing LV remodeling.…”

“…33,34 We have shown that hypoxia-induced histological degeneration was prevented in gp91 À/À mice, suggesting that gp91 phox -containing NADPH oxidase has a crucial role in the pathophysiology of intermittent hypoxia-induced LV remodeling associated with increase in oxidative stress. 5 Pitavastatin significantly reduced the plasma levels of LPO, which were increased by exposure to intermittent hypoxia, without affecting the plasma cholesterol level. Furthermore, the expression levels of 4-HNE and superoxide production in the LV myocardium were also significantly suppressed.…”

“…), for measurement of the right ventricular systolic pressure and LV systolic pressure by a previously reported method. 5 Blood collection was used to measure the plasma levels of lipid peroxide (LPO) and total cholesterol (CHO). The heart was excised, and the upper half was subjected to light-microscopic examination.…”

“…5 Briefly, paraffin sections of the LV myocardium were incubated with a monoclonal antibody for 4-HNE (product No. MHN-20, Japan Institute for the Control of Aging, Shizuoka, Japan) and a secondary antibody (biotinylated anti-mouse IgG), followed by the addition of Vectastain Elite ABC reagent (Vector Laboratories, Burlingame, CA, USA).…”

“…These findings are not observed in mice with knockout of gp91phox, a constituent of NADPH oxidase, which is a major source of reactive oxygen species. 5 Taken together, oxidative stress might be an important target to prevent LV remodeling caused by intermittent hypoxia.…”