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

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.

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

Hypertension ◽

10.1161/01.hyp.36.2.282 ◽

2000 ◽

Vol 36 (2) ◽

pp. 282-290 ◽

Cited By ~ 91

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

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Growth Factor Receptor Transactivation in Mediating End Organ Damage by Angiotensin II

Hypertension ◽

10.1161/01.hyp.0000202497.83294.50 ◽

2006 ◽

Vol 47 (3) ◽

pp. 339-340 ◽

Cited By ~ 4

Author(s):

Hiroyuki Suzuki ◽

Satoru Eguchi

Keyword(s):

Angiotensin Ii ◽

Growth Factor ◽

Growth Factor Receptor ◽

Organ Damage ◽

End Organ Damage ◽

Receptor Transactivation

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Abolition of Hypertension-Induced End-Organ Damage by Androgen Receptor Blockade in Transgenic Rats Harboring the Mouse Ren-2 Gene

Journal of the American Society of Nephrology ◽

10.1097/01.asn.0000033327.65390.ca ◽

2002 ◽

Vol 13 (11) ◽

pp. 2681-2687 ◽

Cited By ~ 42

Author(s):

O. Baltatu

Keyword(s):

Androgen Receptor ◽

Organ Damage ◽

Receptor Blockade ◽

Transgenic Rats ◽

End Organ Damage

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Rapid development of severe end-organ damage in C57BL/6 mice by combining DOCA salt and angiotensin II

Kidney International ◽

10.1038/sj.ki.5002689 ◽

2008 ◽

Vol 73 (5) ◽

pp. 643-650 ◽

Cited By ~ 33

Author(s):

F. Kirchhoff ◽

C. Krebs ◽

U.N. Abdulhag ◽

C. Meyer-Schwesinger ◽

R. Maas ◽

...

Keyword(s):

Angiotensin Ii ◽

Rapid Development ◽

Organ Damage ◽

End Organ Damage

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

The FASEB Journal ◽

10.1096/fasebj.22.1_supplement.923.1 ◽

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

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

Hypertension ◽

10.1161/hyp.78.suppl_1.mp01 ◽

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.

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Abstract P135: 2-methoxyestradiol Minimizes Angiotensin II-induced Hypertension and Renal Dysfunction in Ovariectomized Female and Intact Male Mice

Hypertension ◽

10.1161/hyp.68.suppl_1.p135 ◽

2016 ◽

Vol 68 (suppl_1) ◽

Author(s):

Ajeeth K Pingili ◽

Shyamala Thirunavukkarasu ◽

Nayaab S Khan ◽

Akemi Katsurada ◽

Dewan S Majid ◽

...

Keyword(s):

Angiotensin Ii ◽

Renal Dysfunction ◽

Organ Damage ◽

Ang Ii ◽

Male Mice ◽

Intact Male ◽

Female Mice ◽

End Organ Damage ◽

Induced Hypertension ◽

Post Menopausal

Men and post-menopausal females are more prone to develop hypertension and renal dysfunction as compared to pre-menopausal females. It is well documented that in various experimental models of hypertension, the protection against hypertension in females is lost following ovariectomy (OVX). Recently we have shown that CYP1B1 protects against angiotensin II (Ang II)-induced hypertension and associated cardiovascular changes in female mice, most likely via production of 2-methoxyestradiol (2-ME). This study was conducted to determine if 2-ME reduces Ang II-induced hypertension, renal dysfunction and end organ damage in OVX female, and intact male mice. Treatment of OVX Cyp1b1 +/+ and Cyp1b1 -/- female mice with 2-ME (1.5 mg/kg/day i.p., for 2 weeks) reduced Ang II-induced increase in systolic blood pressure (SBP) (182±5.1 vs. 143± 2.4 mmHg, 179±6.4 vs. 140± 8.6 mmHg, P < 0.05, n= 5), water consumption, urine output and osmolality, and proteinuria (5.5±0.7 vs. 3.3±0.5 mg/24 hrs, 8.4±1.3 vs. 4.4 ±0.9 mg/24 hrs) respectively. 2-ME also reduced Ang II-induced increase in SBP (188±2.6 vs. 143± 2.7 mmHg, P < 0.05, n= 5) in intact male mice. 2-ME did not alter water consumption and urine osmolality, but reduced urine output and sodium excretion, and proteinuria (14.4±2.0 vs. 6.0±0.5 mg/24 hrs) in intact Cyp1b1 +/+ male mice. Treatment with 2-ME attenuated Ang II-induced end-organ damage (actin and collagen accumulation) in OVX Cyp1b1 +/+ and Cyp1b1 -/- female and Cyp1b1 +/+ male mice. 2-ME mitigated urinary excretion of angiotensinogen in OVX Cyp1b1 +/+ and Cyp1b1 -/- female mice infused with Ang II. These data suggest that 2-ME reduces Ang II- induced hypertension and associated renal dysfunction and end-organ damage in OVX Cyp1b1 +/+ and Cyp1b1 -/- female, and intact male mice. Therefore, 2-ME could serve as a therapeutic agent for treatment of hypertension and associated pathogenesis in post-menopausal females, and intact males.

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

Circulation ◽

10.1161/circ.118.suppl_18.s_383-b ◽

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.

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