scholarly journals Interaction of TNF‐α with Angiotensin II contributes to mitochondrial oxidative stress and end organ damage in rats

2008 ◽  
Vol 22 (S1) ◽  
Author(s):  
Nithya Mariappan ◽  
Carrie Elks ◽  
Kayla Prejean ◽  
Srinivas Sriramula ◽  
Joseph Francis
Keyword(s):  
Oxidative Stress ◽  
Angiotensin Ii ◽  
Organ Damage ◽  
Mitochondrial Oxidative Stress ◽  
End Organ Damage ◽  
Tnf Α

Abstract MP01: Deacetylation Of Mitochondrial Cyclophilin D K166 Inhibits Cytokine-induced Oxidative Stress And Attenuates Hypertension

Hypertension ◽  
2021 ◽  
Vol 78 (Suppl_1) ◽  
Author(s):  
Sergey I Dikalov ◽  
Vladimir Mayorov ◽  
Daniel Fehrenbach ◽  
Mingfang Ao ◽  
Alexander Panov ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Angiotensin Ii ◽  
Vascular Function ◽  
Organ Damage ◽  
Cyclophilin D ◽  
Wild Type ◽  
End Organ Damage ◽  
Mitochondrial Superoxide ◽  
Vascular Oxidative Stress

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.

Abstract 1756: Angiotensin II Induced End Organ Damage is Attenuated in Mice Lacking the Gene for TNF: A Mitochondrial Perspective

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Nithya Mariappan ◽  
Srinivas Sriramula ◽  
Joseph Francis
Keyword(s):  
Oxidative Stress ◽  
Blood Pressure ◽  
Angiotensin Ii ◽  
Organ Damage ◽  
Left Ventricular ◽  
Lv Function ◽  
Resonance Spectroscopy ◽  
Cardiac Damage ◽  
Atp Production ◽  
End Organ Damage

Recent findings from our lab and others suggest that the renin-angiotensin system and cytokine interaction contribute to the pathophysiology of cardiovascular disease. In this study, we determined the role played by tumor necrosis factor (TNF) in angiotensin II (ANGII) induced end organ damage at the mitochondrial level. Method : Wild type (WT) and TNF knockout (TNF (−/−)) mice were implanted with osmotic minipumps containing ANG II (1 μg/kg/min) or saline for 14 days. Blood pressure was recorded using telemetry. At the end of the study, left ventricular (LV) function was measured using echocardiography. Mice were sacrificed and the LV was removed and mitochondria isolated for oxidative stress measurement using Electron paramagnetic resonance spectroscopy. Structural integrity of mitochondria was assessed by electron microscopy (EM) and function by measuring mitochondrial redox status. Results: (see table ) ANGII infusion in WT mice resulted in a significant increase in blood pressure and was accompanied by a decrease in fractional shortening. These animals also had increased levels of superoxide and ROS in the LV tissues. The mitochondrial integrity of the cardiomyocytes was damaged both in the isolated mitochondria and tissue as evidenced by EM studies. Mitochondrial superoxide and total ROS were increased and this was accompanied by a decrease in complex activity and reduced ATP production. In contrast, ANGII infusion in TNF (−/−) attenuated cardiac damage, mitochondrial oxidative stress and restored ATP production. Conclusion: ANGII induced cardiac damage is mediated by TNF. These data also demonstrate that ANGII induced increase in TNF inhibits mitochondrial function by affecting electron transport chain activity and indirectly through an increase in oxygen free radicals thereby decreasing ATP synthesis and contributing to end organ damage in hypertension.

Abstract 097: EGF Receptor And ER Stress Mediate End-organ Damage But Not Hypertension Induced By Angiotensin II In Mice

Hypertension ◽  
2014 ◽  
Vol 64 (suppl_1) ◽  
Author(s):  
Katherine J Elliott ◽  
Toshiyuki Tsuji ◽  
Takashi Obama ◽  
Takehiko Takayanagi ◽  
Steven Forrester ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Angiotensin Ii ◽  
Cardiac Hypertrophy ◽  
Er Stress ◽  
Egf Receptor ◽  
Organ Damage ◽  
Ang Ii ◽  
End Organ Damage ◽  
Egfr Activation ◽  
And Oxidative Stress

In cultured vascular smooth muscle cells (VSMC), a metalloprotease ADAM17-dependent EGF receptor (EGFR) activation mediates ERK1/2 activation and subsequent hypertrophy induced by angiotensin II (Ang II). Both ER and oxidative stress are implicated in hypertensive end-organ damage. We hypothesized that pharmacological inhibition of EGFR may prevent end-organ damage but not hypertension in mice infused with Ang II via suppression of ER/oxidative stress. To test this hypothesis, we have evaluated Ang II-induced end-organ damage as well as hypertension in C57Bl/6 mice with or without an EGFR inhibitor erlotinib (20mg/kg/day ip) or ER stress inhibitor 4-phenyl butyric acid (PBA: 1g/kg/day in drinking water). Upon Ang II infusion (1000 ng/kg/min) for 2 weeks, control mice showed phenotypes of cardiac hypertrophy including increased HW/BW ratio (mg/g: 7.9±0.7 vs 5.7±0.6 p<0.01 n=8) and increased LVPWd assessed by cardiac echo (mm: 0.98±0.14 vs 0.69±0.05, p<0.05 n=8) compared with saline infusion. Histological assessments demonstrated medial hypertrophy and perivascular fibrosis of coronary arteries with Ang II infusion. In contrast, cardiac hypertrophy and vascular remodeling were attenuated in mice with Ang II plus erlotinib or PBA; HW/BW ratio (6.8±0.6 or 6.2±0.6 n=8), and cardiac echo (LVPWd: 0.65±0.07 or 0.80±0.07 n=8) compared with saline infusion. Renal fibrosis observed with Ang II infusion was also attenuated in mice with Ang II plus erotinib or PBA. However, Ang II induced similar levels of hypertension in non-treated, erlotinib-treated or PBA-treated mice assessed by telemetry (MAP mmHg: 144±9 vs 149±20 or 139±4). Ang II infusion in mice enhanced ADAM17 and phospho-Tyr EGFR staining in vasculatures of heart and kidney, whereas mice with Ang II plus erlotinib or PBA had diminished phospho-Tyr EGFR staining and no ADAM17 staining in the vasculatures. In addition, IHC analyses revealed less oxidative stress and less ER stress in heart and kidney of Ang II-infused mice with erlotinib or PBA. These data suggest that EGFR activation and subsequent ER stress enhancement are critical for end organ damage via induction of ADAM17 and oxidative stress and is independent from blood pressure regulation.

Abstract 070: AntagomiR-762 Prevents Angiotensin II Induced Aortic Fibrosis and Stiffening

Hypertension ◽  
2015 ◽  
Vol 66 (suppl_1) ◽  
Author(s):  
Kim Ramil C Montaniel ◽  
Jing Wu ◽  
Matthew R Bersi ◽  
Liang Xiao ◽  
Hana A Itani ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Organ Damage ◽  
Matrix Proteins ◽  
Locked Nucleic Acid ◽  
Ang Ii ◽  
End Organ Damage ◽  
Acid Inhibitor ◽  
Vascular Stiffening ◽  
Aortic Stiffening

We and others have shown that hypertension (HTN) is associated with a striking deposition of collagen in the vascular adventitia. This causes vascular stiffening, which increases pulse wave velocity and contributes to end-organ damage. Through a screen of vascular microRNAs (miRNAs), we found that miR-762 is the most upregulated miRNA in mice with angiotensin II (Ang II)-induced HTN. qRT-PCR confirmed that miR-762 is upregulated 6.35±1.22 (p=0.03) fold in aortas of Ang II-infused mice compared with controls. This was a direct effect of Ang II, as miR-762 upregulation was not eliminated by lowering blood pressure with hydralazine and hydrochlorothiazide and was increased only 2-fold in DOCA salt HTN. To study the role of miR-762 in HTN, we administered a locked nucleic acid inhibitor of miR-762 (antagomiR-762). AntagomiR-762 administration did not alter the hypertensive response to Ang II, yet it normalized stress-strain relationships and aortic energy storage that occurs in systole (Table). Further studies showed that antagomiR-762 dramatically affected vascular matrix proteins, reducing mRNA for several collagens and fibronectin and dramatically upregulating collagenases MMP1a, 8 and 13 (Table). Thus, miR-762 has a major role in modulating vascular stiffening and its inhibition dramatically inhibits pathological fibrosis, enhances matrix degradation and normalizes aortic stiffness. AntagomiR-762 might represent a new approach to prevent aortic stiffening and its consequent end-organ damage.

scholarly journals Effect of Bosentan on NF-κB, Inflammation, and Tissue Factor in Angiotensin II–Induced End-Organ Damage

Hypertension ◽  
2000 ◽  
Vol 36 (2) ◽  
pp. 282-290 ◽  
Author(s):  
Dominik N. Muller ◽  
Eero M. A. Mervaala ◽  
Folke Schmidt ◽  
Joon-Keun Park ◽  
Ralf Dechend ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Tissue Factor ◽  
Organ Damage ◽  
End Organ Damage

scholarly journals Ghrelin Pre-treatment Attenuates Local Oxidative Stress and End Organ Damage During Cardiopulmonary Bypass in Anesthetized Rats

2018 ◽  
Vol 9 ◽  
Author(s):  
Vijayakumar Sukumaran ◽  
Hirotsugu Tsuchimochi ◽  
Yutaka Fujii ◽  
Hiroshi Hosoda ◽  
Kenji Kangawa ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Cardiopulmonary Bypass ◽  
Organ Damage ◽  
End Organ Damage ◽  
Anesthetized Rats ◽  
Pre Treatment

Abstract 1476: Angiotensin II Induced Hypertrophic Response And Oxidative Stress Is Attenuated In Mice Lacking The Gene For Tnf-α

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Srinivas Sriramula ◽  
Nithya Mariappan ◽  
Elizabeth McILwain ◽  
Joseph Francis
Keyword(s):  
Oxidative Stress ◽  
Angiotensin Ii ◽  
Cardiac Hypertrophy ◽  
Collagen Type ◽  
Resonance Spectroscopy ◽  
Type I ◽  
Ang Ii ◽  
Hypertrophic Response ◽  
Tnf Α ◽  
And Oxidative Stress

Tumor necrosis factor-alpha (TNF-α) and angiotensin II (Ang II) play an important role in the pathophysiology of cardiovascular disease in part by inducing the cardiac hypertrophic response and oxidative stress. Recently we demonstrated that angiotensin induced hypertensive response is attenuated in mice lacking the gene for TNF-α. In this study, we examined whether Ang II induced cardiac hypertrophy and increased oxidative stress is mediated through TNF-α. Methods and results: Male TNF-α (−/−) and age matched control (WT) mice were subcutaneously implanted with osmotic minipumps containing Ang II (1 μg/kg/min) or saline for 14 days. Human recombinant TNF-α was injected in one group of TNF-α (−/−) mice (10 μg/kg/day) for 14 days. In WT+Ang mice, a temporal increase in blood pressure was observed during the study as measured by radio telemetry transmitters. At the end of the study, echocardiography revealed an increase in thickness and dimensions of left ventricle (LV) and decreased fractional shortening (%FS) in WT+Ang mice. Real time RT-PCR showed that Ang II- infusion resulted in an increase in heart/bodyweight ratio and of cardiac hypertrophy markers ANP and BNP, and profibrotic genes Collagen Type I, Collagen Type II, and TGF-β in WT mice. Electron Spin resonance spectroscopy revealed an increase in total ROS, superoxide and peroxynitrite in the WT+ANG mice when compared to control WT mice. However, these changes were all attenuated in TNF-α (−/−)+Ang mice. Ang II infusion also increased significantly the mRNA expression of gp91Phox, NOX-1, NOX-4 and AT1R in the LV of WT mice, but not in TNF-α (−/−) mice. Interestingly, injection of TNF-α in the TNF-α (−/−) mice, treated with Ang II resulted in increased cardiac hypertrophy and oxidative stress. Conclusions: Findings from the present study suggest that TNF-α plays an important role in the development of cardiac hypertrophy and oxidative stress in Ang II-induced hypertension.

Abstract P074: Mitochondrial Isolevuglandins Contribute To Vascular Oxidative Stress And Mitochondria-targeted Scavenger Of Isolevuglandins Reduces Mitochondrial Dysfunction And Hypertension

Hypertension ◽  
2020 ◽  
Vol 76 (Suppl_1) ◽  
Author(s):  
Anna Dikalova ◽  
Vladimir Mayorov ◽  
Liang Xiao ◽  
Alexander Panov ◽  
Venkataraman Amarnath ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Angiotensin Ii ◽  
Mitochondrial Dysfunction ◽  
Vascular Function ◽  
Therapeutic Potential ◽  
Protein Adducts ◽  
Specific Marker ◽  
Mitochondrial Oxidative Stress ◽  
Major Health Problem ◽  
Multiple Drugs

Hypertension remains a major health problem in Western Societies, and blood pressure is poorly controlled in a third of patients despite use of multiple drugs. Mitochondrial dysfunction contributes to hypertension and mitochondria-targeted agents can potentially improve treatment of hypertension. We have proposed that mitochondrial oxidative stress produces reactive dicarbonyl lipid peroxidation products isolevuglandins (isoLGs) and that scavenging of mitochondrial isoLG improves vascular function and reduces hypertension. To test this hypothesis, we have studied the accumulation of mitochondrial isoLG-protein adducts in human patients with essential hypertension and angiotensin II mouse model of hypertension using mass spectrometry and Western blot analysis. The therapeutic potential of targeting mitochondrial isoLG was tested by the novel mitochondria-targeted isoLG scavenger, mito2HOBA. Mitochondrial isoLG in arterioles isolated from hypertensive patients were 250% greater than in arterioles from normotensive subjects, and ex vivo mito2HOBA treatment of arterioles from hypertensive subjects improved deacetylation of a key mitochondrial antioxidant, superoxide dismutase 2 (SOD2). In human aortic endothelial cells, mito2HOBA diminished mitochondrial superoxide and inhibited cardiolipin oxidation, a specific marker of mitochondrial oxidative stress. In angiotensin II-infused mice, mito2HOBA prevented accumulation of mitochondrial isoLG-protein adducts, improved Sirt3 mitochondrial deacetylase activity, reduced vascular superoxide, increased endothelial nitric oxide, improved endothelium-dependent relaxation, and attenuated hypertension. Mito2HOBA preserved mitochondrial respiration, protected ATP production, and reduced mitochondrial permeability pore opening in angiotensin II-infused mice. These data support the role of mitochondrial isoLGs in endothelial dysfunction and hypertension. We conclude that scavenging of mitochondrial isoLGs may have therapeutic potential in treatment of vascular dysfunction and hypertension.

scholarly journals Tobacco smoking induces cardiovascular mitochondrial oxidative stress, promotes endothelial dysfunction, and enhances hypertension

2019 ◽  
Vol 316 (3) ◽  
pp. H639-H646 ◽  
Author(s):  
Sergey Dikalov ◽  
Hana Itani ◽  
Bradley Richmond ◽  
Liaison Arslanbaeva ◽  
Aurelia Vergeade ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Angiotensin Ii ◽  
Endothelial Dysfunction ◽  
Cigarette Smoke ◽  
Tobacco Smoke ◽  
Tobacco Smoking ◽  
Smoke Exposure ◽  
Metabolic Reprogramming ◽  
Wild Type ◽  
Mitochondrial Oxidative Stress

Tobacco smoking is a major risk factor for cardiovascular disease and hypertension. It is associated with the oxidative stress and induces metabolic reprogramming, altering mitochondrial function. We hypothesized that cigarette smoke induces cardiovascular mitochondrial oxidative stress, which contributes to endothelial dysfunction and hypertension. To test this hypothesis, we studied whether the scavenging of mitochondrial H2O2 in transgenic mice expressing mitochondria-targeted catalase (mCAT) attenuates the development of cigarette smoke/angiotensin II-induced mitochondrial oxidative stress and hypertension compared with wild-type mice. Two weeks of exposure of wild-type mice with cigarette smoke increased systolic blood pressure by 17 mmHg, which was similar to the effect of a subpresssor dose of angiotensin II (0.2 mg·kg−1·day−1), leading to a moderate increase to the prehypertensive level. Cigarette smoke exposure and a low dose of angiotensin II cooperatively induced severe hypertension in wild-type mice, but the scavenging of mitochondrial H2O2 in mCAT mice completely prevented the development of hypertension. Cigarette smoke and angiotensin II cooperatively induced oxidation of cardiolipin (a specific biomarker of mitochondrial oxidative stress) in wild-type mice, which was abolished in mCAT mice. Cigarette smoke and angiotensin II impaired endothelium-dependent relaxation and induced superoxide overproduction, which was diminished in mCAT mice. To mimic the tobacco smoke exposure, we used cigarette smoke condensate, which induced mitochondrial superoxide overproduction and reduced endothelial nitric oxide (a hallmark of endothelial dysfunction in hypertension). Western blot experiments indicated that tobacco smoke and angiotensin II reduce the mitochondrial deacetylase sirtuin-3 level and cause hyperacetylation of a key mitochondrial antioxidant, SOD2, which promotes mitochondrial oxidative stress. NEW & NOTEWORTHY This work demonstrates tobacco smoking-induced mitochondrial oxidative stress, which contributes to endothelial dysfunction and development of hypertension. We suggest that the targeting of mitochondrial oxidative stress can be beneficial for treatment of pathological conditions associated with tobacco smoking, such as endothelial dysfunction, hypertension, and cardiovascular diseases. Listen to this article’s corresponding podcast at https://ajpheart.podbean.com/e/mitochondrial-oxidative-stress-in-smoking-and-hypertension/ .

scholarly journals Cyclosporin A Protects Against Angiotensin II–Induced End-Organ Damage in Double Transgenic Rats Harboring Human Renin and Angiotensinogen Genes

Hypertension ◽  
2000 ◽  
Vol 35 (1) ◽  
pp. 360-366 ◽  
Author(s):  
Eero Mervaala ◽  
Dominik N. Müller ◽  
Joon-Keun Park ◽  
Ralph Dechend ◽  
Folke Schmidt ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Cyclosporin A ◽  
Organ Damage ◽  
Transgenic Rats ◽  
End Organ Damage ◽  
Human Renin
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