Role of p47
            
              phox
            
            in Vascular Oxidative Stress and Hypertension Caused by Angiotensin II

We have previously reported that depletion Cyclophilin D (CypD), a regulatory subunit of mitochondrial permeability transition pore, improves vascular function and attenuates hypertension, however, specific regulation of CypD in hypertension is not clear. Analysis of human arterioles from hypertensive patients did not reveal alterations in CypD levels but showed 3-fold increase in CypD acetylation. We hypothesized that CypD-K166 acetylation promotes vascular oxidative stress and hypertension, and measures to reduce CypD acetylation can improve vascular function and reduce hypertension. Essential hypertension and animal models of hypertension are linked to inactivation of mitochondrial deacetylase Sirt3 by highly reactive lipid oxidation products, isolevuglandins (isoLGs), and supplementation of mice with mitochondria targeted scavenger of isoLGs, mito2HOBA, improves CypD deacetylation. To test the specific role of CypD-K166 acetylation, we developed CypD-K166R deacetylation mimic mutant mice. Mitochondrial respiration, vascular function and systolic blood pressure in CypD-K166R mice was similar to wild-type C57Bl/6J mice. Meanwhile, angiotensin II-induced hypertension was substantially attenuated in CypD-K166R mice (144 mmHg) compared with wild-type mice (161 mmHg). Angiotensin II infusion in wild-type mice significantly increased mitochondrial superoxide, impaired endothelial dependent relaxation, and reduced the level of endothelial nitric oxide which was prevented in angiotensin II-infused CypD-K166R mice. Hypertension is linked to increased levels of inflammatory cytokines TNFα and IL-17A promoting vascular oxidative stress and end-organ damage. We have tested if CypD-K166R mice are protected from cytokine-induced oxidative stress. Indeed, ex vivo incubation of aorta with the mixture of angiotensin II, TNFα and IL-17A (24 hours) increased mitochondrial superoxide by 2-fold in wild-type aortas which was abrogated in CypD-K166R mice. These data support the pathophysiological role of CypD acetylation in inflammation, oxidative stress and hypertensive end-organ damage. We propose that targeting CypD acetylation may have therapeutic potential in treatment of vascular dysfunction and hypertension.

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Abstract P080: Mutation Of Lysine 68 To Arginine Mimics Deacetylation Of Mitochondrial Superoxide Dismutase, Protects From Vascular Oxidative Stress And Attenuates Angiotensin II-Induced Hypertension

Hypertension ◽

10.1161/hyp.76.suppl_1.p080 ◽

2020 ◽

Vol 76 (Suppl_1) ◽

Author(s):

Anna Dikalova ◽

Liliya Tkachuk ◽

Marcos G Lopez ◽

Frederic T Billings ◽

Sergey I Dikalov

Keyword(s):

Oxidative Stress ◽

Blood Pressure ◽

Superoxide Dismutase ◽

Angiotensin Ii ◽

Wild Type ◽

Mitochondrial Superoxide ◽

Induced Hypertension ◽

Lysine Residues ◽

Vascular Oxidative Stress

By recent guidelines, almost one-half of adults have hypertension, and blood pressure is poorly controlled in a third of patients despite use of multiple drugs, likely due to mechanisms contributing to blood pressure elevation that are not affected by current treatments. Hypertension is linked to oxidative stress; however, common antioxidants are ineffective. We found that hypertension is associated with inactivation of key mitochondrial antioxidant, superoxide dismutase 2 (SOD2), due to acetylation of lysine residues at the catalytic center. The role of specific SOD2 lysine residues in hypertension, however, has not been defined. We proposed that inactivation of key intrinsic antioxidant, SOD2, in hypertension is linked to acetylation of Lysine 68, and mutation of K68 to Arginine mimics SOD2 deacetylation, inhibits vascular oxidative stress and attenuates angiotensin II-induced hypertension. To test this hypothesis, we have investigated SOD2 acetylation in arterioles from patients with essential hypertension and developed a new deacetylation mimic SOD2 mutant K68R mice (SOD2-K68R). Western blot analysis of arterioles isolated from human mediastinal fat showed 3-fold increase in SOD2 acetylation in hypertensive patients compared with normotensive subjects while SOD2 levels were not affected. To define the functional significance of K68 acetylation we performed studies in vivo in SOD2-K68R mice using angiotensin II model of vascular dysfunction and hypertension. Angiotensin II infusion in wild-type C57Bl/6J mice induced vascular inflammation and oxidative stress, and increased blood pressure to 160 mm Hg. Mutation of Lysine 68 to Arginine in SOD2-K68R mice completely prevented the increase in mitochondrial superoxide and significantly attenuated the angiotensin II induced hypertension (135 mm Hg). Angiotensin II and TNFα co-operatively induce SOD2 acetylation and hypertension. Treatment of wild-type aortas with angiotensin II and TNFα in organoid culture increased mitochondrial superoxide by 2-fold which was completely prevented in aortas isolated from SOD2-K68R mice. These data support an important role of SOD2-K68 acetylation in hypertension, and strategies to reduce mitochondrial acetylation may have therapeutic potential.

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Higher Angiotensin II type 1 receptor (AT1R) levels and activity in the post-mortem brains of older persons with Alzheimer's disease

The Journals of Gerontology Series A ◽

10.1093/gerona/glab376 ◽

2021 ◽

Author(s):

Caglar Cosarderelioglu ◽

Lolita S Nidadavolu ◽

Claudene J George ◽

Ruth Marx ◽

Laura Powell ◽

...

Keyword(s):

Oxidative Stress ◽

Angiotensin Ii ◽

Amyloid Β ◽

Renin Angiotensin System ◽

Angiotensin Receptors ◽

Post Mortem ◽

Protein Levels ◽

Normal Individuals ◽

Markers Of Oxidative Stress

Abstract Aging is a key risk factor in Alzheimer's dementia (AD) development and progression. The primary dementia-protective benefits of Angiotensin II subtype 1 receptor (AT1R) blockers are believed to arise from systemic effects on blood pressure. However, a brain-specific renin-angiotensin system (b-RAS) exists, which can be altered by AT1R blockers. Brain RAS acts mainly through three angiotensin receptors: AT1R, AT2R, and AT4R. Changes in these brain angiotensin receptors may accelerate the progression of AD. Using post-mortem frontal cortex brain samples of age- and sex-matched cognitively normal individuals (n = 30) and AD patients (n = 30), we sought to dissect the b-RAS changes associated with AD and assess how these changes correlate with brain markers of oxidative stress, inflammation, and mitochondrial dysfunction as well as amyloid-β and paired helical filament tau pathologies. Our results show higher protein levels of the pro-inflammatory AT1R and phospho-ERK (pERK) in the brains of AD participants. Brain AT1R levels and pERK correlated with higher oxidative stress, lower cognitive performance, and higher tangle and amyloid-β scores. This study identifies molecular changes in b-RAS and offers insight into the role of b-RAS in AD-related brain pathology.

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ROLE OF CYCLOOXYGENASE-2 PATHWAY IN ANTI-OXIDATIVE EFFECT OF ASPIRIN AND IN ANGIOTENSIN II-INDUCED OXIDATIVE STRESS: PP.29.160

Journal of Hypertension ◽

10.1097/01.hjh.0000379698.14771.d8 ◽

2010 ◽

Vol 28 ◽

pp. e497

Author(s):

R Wu ◽

J de Champlain ◽

H Girouard

Keyword(s):

Oxidative Stress ◽

Angiotensin Ii ◽

Cyclooxygenase 2 ◽

Oxidative Effect

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Modulation of Gi Proteins in Hypertension: Role of Angiotensin II and Oxidative Stress

Current Cardiology Reviews ◽

10.2174/157340310793566046 ◽

2010 ◽

Vol 6 (4) ◽

pp. 298-308 ◽

Cited By ~ 8

Author(s):

Madhu B. Anand-Srivastava

Keyword(s):

Oxidative Stress ◽

Angiotensin Ii ◽

And Oxidative Stress ◽

Gi Proteins

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Oxidative stress and endothelial dysfunction

Hämostaseologie ◽

10.1055/s-0037-1616894 ◽

2007 ◽

Vol 27 (01) ◽

pp. 5-12 ◽

Cited By ~ 18

Author(s):

G. Muller ◽

C. Goettsch ◽

H. Morawietz

Keyword(s):

Oxidative Stress ◽

Endothelial Dysfunction ◽

Vascular Function ◽

Vessel Wall ◽

Clinical Implications ◽

Oxygen Species ◽

Vascular Oxidative Stress ◽

Arteries And Veins ◽

Different Sources

SummaryThis review focuses on the role of vascular oxidative stress in the development and progression of endothelial dysfunction. We discuss different sources of oxidative stress in the vessel wall, oxidative stress and coagulation, the role of oxidative stress and vascular function in arteries and veins, the flow-dependent regulation of reactive oxygen species, the putative impact of oxidative stress on atherosclerosis, the interaction of angiotensin II, oxidative stress and endothelial dysfunction, and clinical implications.

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