Abstract
Exposure to microgravity results in post-flight cardiovascular deconditioning and orthostatic intolerance in astronauts. Vascular oxidative stress injury and mitochondrial dysfunction have been indicated in this process. To elucidate the mechanism for this condition, we investigated whether mitochondria regulated NADPH oxidase in hindlimb unweighting (HU) rat cerebral and mesenteric arteries. Four-week HU was used to simulate microgravity in rats. Vascular superoxide generation, protein and mRNA levels of Nox2/Nox4, and the activity of NADPH oxidase were examined in the present study. Compared with control rats, the levels of superoxide increased in cerebral (P<0.001) but not in mesenteric vascular smooth muscle cells. The protein and mRNA levels of Nox2 and Nox4 were upregulated significantly (P<0.001 and P<0.001 for Nox2, respectively; P<0.001 and P<0.001 for Nox4, respectively) in HU rat cerebral arteries but not in mesenteric arteries. NADPH oxidases were activated significantly by HU (P<0.001) in cerebral arteries but not in mesenteric arteries. Chronic treatment with mitochondria-targeted antioxidant mitoTEMPO attenuated superoxide levels (P<0.001), decreased the protein and mRNA expression levels of Nox2/Nox4 (P<0.01 and P<0.05 for Nox2, respectively; P<0.001 and P<0.001 for Nox4, respectively) and the activity of NADPH oxidase (P<0.001) in HU rat cerebral arteries, but exerted no effects on HU rat mesenteric arteries. Therefore, mitochondria regulated the expression and activity of NADPH oxidases during simulated microgravity. Both mitochondria and NADPH oxidase participated in vascular redox status regulation.
Highlights
Exposure to microgravity results in post-flight cardiovascular deconditioning and orthostatic intolerance in astronauts
Effects of hindlimb unweighting (HU) on Vascular Reactive Oxygen Species To investigate whether HU altered the redox status of rat cerebral and mesenteric arterial vascular smooth muscle cells (VSMCs), we detected superoxide levels using DHE and high-performance liquid chromatography (HPLC)-based method (Figure 1 and Figure 2)
The present study provided, for the first time to the best of the authors’ knowledge, three important findings: (1) mitochondriatargeted antioxidant mitoTEMPO attenuated HU rat cerebrovascular oxidative stress injury; (2) mRNA and protein expression levels of Nox2 and Nox4 increased in HU rat cerebral arteries, which were restored by mitoTEMPO; and (3) the total activity of NADPH oxidases increased in HU rat cerebral arteries, which was restored by mitoTEMPO
Summary
Exposure to microgravity results in post-flight cardiovascular deconditioning and orthostatic intolerance in astronauts. The animal-based studies have confirmed the differential structural and functional changes in hindlimb unweighting (HU) rat cerebral and mesenteric arteries [1,2]. The roles of oxidative stress injury caused by reactive oxygen species (ROS) in vascular structural and functional remodeling have been well established in cardiovascular and metabolic disorders [3,4]. Our previous work found that superoxide levels increased in HU rat cerebral arteries, which could be attributed to the activated local renin-angiotensin system [10]. We found that NADPH oxidase inhibition with apocynin reversed abnormal vascular responses to vasoconstrictors and vasodilators, and these effects were related to the regulation of the nitric oxide synthase (NOS)-NO system in HU rat cerebral arteries [11]. The characteristics of expression and activity of NADPH oxidases are unknown
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