Deletion of Superoxide Dismutase 1 Blunted Inflammatory Aortic Remodeling in Hypertensive Mice under Angiotensin II Infusion (original) (raw)
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Role of Vascular Extracellular Superoxide Dismutase in Hypertension
Hypertension, 2011
Previous studies indicate that superoxide is important in the modulation of blood pressure but have not specifically identified the cell types or organs involved. We created mice with loxP sites flanking the extracellular superoxide dismutase (SOD3) gene. These mice were crossed with mice expressing inducible Cre-recombinase driven by the smooth muscle myosin heavy chain promoter allowing tissue-specific deletion of SOD3. Deletion of SOD3 increased vascular superoxide and reduced vascular NO levels as detected by electron spin resonance. Despite these changes in NO and superoxide, we did not observe increases in vascular inflammation caused by angiotensin II. Moreover, deletion of vascular SOD3 did not augment hypertension in response to angiotensin II. In additional studies, we also deleted SOD3 from the circumventricular organs by intracerebroventricular injection of an adenovirus encoding Cre-recombinase. Although this raised blood pressure and augmented the hypertension caused b...
Role of NADH/NADPH Oxidase-Derived H2O2 in Angiotensin II-Induced Vascular Hypertrophy
Recent evidence suggests that oxidative mechanisms may be involved in vascular smooth muscle cell (VSMC) hypertrophy. We previously showed that angiotensin II (Ang II) increases superoxide production by activating an NADH/NADPH oxidase, which contributes to hypertrophy. In this study, we determined whether Ang II stimulation of this oxidase results in H 2 O 2 production by studying the effects of Ang II on intracellular H 2 O 2 generation, intracellular superoxide dismutase and catalase activity, and hypertrophy. Ang II (100 nmol/L) significantly increased intracellular H 2 O 2 levels at 4 hours. Neither superoxide dismutase activity nor catalase activity was affected by Ang II; the SOD present in VSMCs is sufficient to metabolize Ang II-stimulated superoxide to H 2 O 2 , which accumulates more rapidly than it is degraded by catalase. This increase in H 2 O 2 was inhibited by extracellular catalase, diphenylene iodonium, an inhibitor of the NADH/NADPH oxidase, and the AT 1 receptor blocker losartan. In VSMCs stably transfected with antisense p22phox, a critical component of the NADH/NADPH oxidase in which oxidase activity was markedly reduced, Ang II-induced production of H 2 O 2 was almost completely inhibited, confirming that the source of Ang II-induced H 2 O 2 was the NADH/NADPH oxidase. Using a novel cell line that stably overexpresses catalase, we showed that this increased H 2 O 2 is a critical step in VSMC hypertrophy, a hallmark of many vascular diseases. Inhibition of intracellular superoxide dismutase by diethylthiocarbamate (1 mmol/L) also resulted in attenuation of Ang II-induced hypertrophy (62Ϯ2% inhibition). These data indicate that AT 1 receptor-mediated production of superoxide generated by the NADH/NADPH oxidase is followed by an increase in intracellular H 2 O 2 , suggesting a specific role for these oxygen species and scavenging systems in modifying the intracellular redox state in vascular growth. (Hypertension. 1998;32:488-495.) Key Words: vascular smooth muscle Ⅲ angiotensin II Ⅲ NADH Ⅲ NADPH oxidase Ⅲ hydrogen peroxide Ⅲ superoxide dismutase Ⅲ catalase Ⅲ hypertrophy
Role of NADH/NADPH Oxidase–Derived H 2 O 2 in Angiotensin II–Induced Vascular Hypertrophy
Hypertension, 1998
Recent evidence suggests that oxidative mechanisms may be involved in vascular smooth muscle cell (VSMC) hypertrophy. We previously showed that angiotensin II (Ang II) increases superoxide production by activating an NADH/NADPH oxidase, which contributes to hypertrophy. In this study, we determined whether Ang II stimulation of this oxidase results in H 2 O 2 production by studying the effects of Ang II on intracellular H 2 O 2 generation, intracellular superoxide dismutase and catalase activity, and hypertrophy. Ang II (100 nmol/L) significantly increased intracellular H 2 O 2 levels at 4 hours. Neither superoxide dismutase activity nor catalase activity was affected by Ang II; the SOD present in VSMCs is sufficient to metabolize Ang II-stimulated superoxide to H 2 O 2 , which accumulates more rapidly than it is degraded by catalase. This increase in H 2 O 2 was inhibited by extracellular catalase, diphenylene iodonium, an inhibitor of the NADH/NADPH oxidase, and the AT 1 receptor blocker losartan. In VSMCs stably transfected with antisense p22phox, a critical component of the NADH/NADPH oxidase in which oxidase activity was markedly reduced, Ang II-induced production of H 2 O 2 was almost completely inhibited, confirming that the source of Ang II-induced H 2 O 2 was the NADH/NADPH oxidase. Using a novel cell line that stably overexpresses catalase, we showed that this increased H 2 O 2 is a critical step in VSMC hypertrophy, a hallmark of many vascular diseases. Inhibition of intracellular superoxide dismutase by diethylthiocarbamate (1 mmol/L) also resulted in attenuation of Ang II-induced hypertrophy (62Ϯ2% inhibition). These data indicate that AT 1 receptor-mediated production of superoxide generated by the NADH/NADPH oxidase is followed by an increase in intracellular H 2 O 2 , suggesting a specific role for these oxygen species and scavenging systems in modifying the intracellular redox state in vascular growth. (Hypertension. 1998;32:488-495.
Hypertension, 2010
The circumventricular organs (CVO) lack a well-formed blood-brain barrier and produce superoxide (O 2 •− ) in response to angiotensin II and other hypertensive stimuli. This increase in central O 2 •− has been implicated in regulation of blood pressure. The extracellular superoxide dismutase (SOD3) is highly expressed in cells associated with CVO, and particularly with tanycytes lining this region. To understand the role of SOD3 in the CVO in blood pressure regulation, we performed intracerebroventricular (ICV) injection an adenovirus encoding Cre-recombinase (AdCre, 5×10 8 particles/ml) in mice with loxP sites flanking the SOD3 coding region (SOD3 loxp/loxp mice). An adenovirus encoding red-fluorescent protein (AdRFP) was injected as a control. Deletion of CVO SOD3 increased baseline blood pressure modestly and markedly augmented the hypertensive response to low-dose angiotensin II (140 ng/kg/day), while ICV injection of AdRFP had minimal effects on these parameters. AdCre treated mice exhibited increased sympathetic modulation of heart rate and blood pressure variability, increased vascular superoxide production and T cell activation as characterized by increased circulating CD69+/CD3+ cells. Deletion of CVO SOD3 also markedly increased vascular T cell and leukocyte infiltration caused by angiotensin II. We conclude that SOD3 in the CVO plays a critical role in regulation of blood pressure and its loss promotes T cell activation and vascular inflammation, in part by modulating sympathetic outflow. These findings provide insight into how central signals produce vascular inflammation in response to hypertensive stimuli such as angiotensin II.
Elevation of oxidative stress in the aorta of genetically hypertensive mice
Mechanisms of Ageing and Development, 2003
Hypertension is an age-dependent disorder. Oxidative stress has been suggested to play a role in aging and age-dependent disorders. The objective of this study is to examine the oxidant and antioxidant status in the aorta of a mouse model with high blood pressure (BPH). Our results showed that the level of malondialdehyde (MDA) in the aorta of BPH mice was approximately 2.6-fold higher than that of the normal blood pressure (BPN) mice, suggesting an increased in vivo oxidative stress in the arterial wall of BPH mice. In addition, the release of hydrogen peroxide (H 2 O 2 ) from the aorta of BPH mice was significantly faster than that of BPN mice. To determine if the increased H 2 O 2 release is related to a down-regulation of antioxidant enzymes in the arterial wall, we measured the activities of the major antioxidant enzymes in mouse aortas. We observed that the activities of Cu/Zn-superoxide dismutase (SOD) and glutathione peroxidase-1 in BPH mice were similar to BPN mice. On the other hand, the catalase activity in the aorta of BPH mice was significantly reduced while the activities of Mn-SOD and extracellular (EC)-SOD in the aorta of BPH mice were significantly elevated as compared with BPN mice. These results suggest that increase in SOD activity and decrease in catalase activity might be responsible for the increased release of H 2 O 2 in the arterial wall of BPH mice. #
Cardiovascular Research, 1999
Background: Angiotensin II (ANG II) mediated hypertension accelerates atherosclerosis (AS) and thereby increases the incidence of 2 myocardial infarction (MI). On the other hand, superoxide anion (O ) is involved in the modification of low density lipoproteins, 2 inhibition of prostacyclin (PGI ) formation and breakdown of nitric oxide. These events finally lead to rapid progression of AS and MI. In 2 2 the present study, we investigate whether ANG II can induce O release from human vascular endothelial cells (HVECs) and the possible 2 mechanisms involved. Methods and Results: The expression of ANG receptors subtype-1 (AT-1) and subtype-2 (AT-2) were identified 2 by using reverse transcription polymerase chain reaction and sequence analysis. The O production was dose-dependently increased in 2 27 29
Pharmacological induction of vascular extracellular superoxide dismutase expression in vivo
Journal of Cellular and Molecular Medicine, 2009
Nitric oxide exhibits a variety of anti-atherogenic effects such as vasodilation, anti-aggregation, anti-apoptosis, anti-adhesion, antiproliferation and antioxidation [1]. In common conditions such as hypertension, coronary artery disease and type 2 diabetes, the bioavailability of nitric oxide is reduced, as demonstrated by blunted endothelium-dependent vasodilation . Such endothelial dysfunction is likely a consequence of increased vascular oxidative stress, a condition characterized by a misbalance of endogenous production of vascular reactive oxygen species (ROS) and the vascular antioxidative capacity. Although a variety of mediators have been described to contribute to vascular oxidative stress, both the generation and the detoxification of superoxide most likely play a major role in this process.