Telmisartan ameliorates oxidative stress and apoptosis in the liver of rats exposed to chronic intermittent hypoxia

Abstract

BACKGROUND AND HYPOTHESIS: Recurrent cycles of severe hypoxia and reoxygenation are a hallmark feature of obstructive sleep apnea (OSA) syndrome, resulting in chronic intermittent hypoxia (IH) that causes excessive production of reactive oxygen species and oxidative stress in tissues and organs. It has been shown that blockade of angiotensin (AT) receptors alleviated the IH-induced systemic hypertension. However, the mechanistic involvement of AT receptors in the pathogenesis of liver injury under chronic IH condition is currently unknown. We hypothesized that the expression of NADPH oxidase induced by activation of AT receptor type 1 plays a role in the IH-induced oxidative stress and apoptosis in the rat liver. METHODOLOGY: Adult Sprague-Dawley rats were exposed to air for normoxic (Nx) control or to normobaric oxygen levels alternating between 5-21% 8 hr/day for IH treatment for 2 weeks. Rats were fed with an AT1 receptor blocker telmisartan (10 mg/kg body weight), or vehicle daily before the hypoxic treatment. The mRNA levels of NADPH oxidase subunits (p22-phox and NOX-4), the pro-apoptotic genes (BAX and FAS) and anti-apoptotic gene (Bcl-2) were examined by RT-PCR; the cell apoptosis was detected by TUNEL assay; also the level of oxidative stress with malondialdehyde (MDA) in the liver. RESULTS: Our results showed that the MDA level and the mRNA levels of p22-phox, NOX-4, BAX, FAS and also the amount of TUNEL-positive cells were significantly increased in the hypoxic group, when compared with the Nx and telmisartan-treated hypoxic (TIH) groups. In addition, the expression of anti-apoptotic gene Bcl-2 was decreased significantly in the hypoxic group than those of the Nx and TIH groups. SUMMARY AND CONCLUSION: Blockade of the AT1 receptor with telmisartan mitigates oxidative stress and apoptosis in the liver of rats exposed to chronic IH, thus supporting a pathogenic role of NADPH oxidase induced by AT1 receptor activation in the hepatic injury in chronic IH resembling a severe OSA condition.