Abstract 15326: Inactivation of Mitochondrial Deacetylase Sirt3 Induces Oxidative Stress, Promotes Vascular Hypertrophy, Increases Aortic Dissections, Exacerbates Hypertension and Mortality

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Anna Dikalova ◽  
Sergey Gutor ◽  
Vasiliy Polosukhin ◽  
Sergey Dikalov
Keyword(s):  
Oxidative Stress ◽  
Nitric Oxide ◽  
Cardiovascular Disease ◽  
Smooth Muscle ◽  
Angiotensin Ii ◽  
Aortic Dissection ◽  
Vascular Dysfunction ◽  
Vascular Hypertrophy ◽  
Abdominal Aortic ◽  
Aortic Dissections

Introduction: Vascular dysfunction plays a key role in hypertension and cardiovascular disease, which causes one-third of deaths worldwide. Mitochondrial dysfunction contributes to these conditions; however, specific mechanisms are not clear. We showed inactivation of mitochondrial deacetylase Sirt3 in arterioles from patients with essential hypertension associated with superoxide dismutase inactivation, vascular inflammation and oxidative stress. Hypothesis: We hypothesized that the loss of vascular Sirt3 induces oxidative stress, promotes vascular dysfunction and hypertension. Methods: To test this hypothesis, we developed tamoxifen-inducible smooth muscle specific Sirt3 knockout mice (SmcSirt3KO) by crossing the Sirt3flox/flox mice with mice carrying a gene for inducible Cre in the vascular smooth muscle cells. Results and Discussion: Hypertension was modestly increased but considerably increased mortality in angiotensin II-infused SmcSirt3KO mice (35% vs 5% in WT) which was associated with higher rate of aortic dissections (50% vs 10% in WT). The basal superoxide and nitric oxide levels were not affected in SmcSirt3KO mice, however, angiotensin II infusion significantly increased superoxide and nitric oxide inactivation in SmcSirt3KO mice compared with wild-type mice supporting the pathological role of smooth muscle Sirt3 impairment. Post-mortem analysis showed high frequency of abdominal aortic aneurysms in angiotensin II-infused SmcSirt3KO mice suggesting that adverse vascular remodeling contributed to high mortality in these mice. To gain further insight into vascular pathology we performed histological examination using Verhoeff-van Gieson staining. Angiotensin II-infused SmcSirt3KO mice had 5-time higher abdominal aortic dissections rate, increased vascular hypertrophy, and disrupted elastic lamellae. Conclusion: Aortic dissection is a catastrophic disease with high mortality and morbidity characterized by fragmentation of elastin and smooth muscle cell dysfunction. Our data suggest that Sirt3 impairment can contribute to vascular hypertrophy, aortic dissection, end-organ-damage and mortality. It is conceivable that targeting Sirt3 may have therapeutic potential in cardiovascular disease.

scholarly journals Soluble guanylyl cyclase is a target of angiotensin II-induced nitrosative stress in a hypertensive rat model

2012 ◽  
Vol 303 (5) ◽  
pp. H597-H604 ◽  
Author(s):  
Pierre-Antoine Crassous ◽  
Samba Couloubaly ◽  
Can Huang ◽  
Zongmin Zhou ◽  
Padmamalini Baskaran ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Smooth Muscle ◽  
Angiotensin Ii ◽  
Guanylyl Cyclase ◽  
Vascular Reactivity ◽  
Nitrosative Stress ◽  
Vascular Dysfunction ◽  
Soluble Guanylyl Cyclase ◽  
Smooth Muscle Relaxation ◽  
Ang Ii

Nitric oxide (NO) by activating soluble guanylyl cyclase (sGC) is involved in vascular homeostasis via induction of smooth muscle relaxation. In cardiovascular diseases (CVDs), endothelial dysfunction with altered vascular reactivity is mostly attributed to decreased NO bioavailability via oxidative stress. However, in several studies, relaxation to NO is only partially restored by exogenous NO donors, suggesting sGC impairment. Conflicting results have been reported regarding the nature of this impairment, ranging from decreased expression of one or both subunits of sGC to heme oxidation. We showed that sGC activity is impaired by thiol S-nitrosation. Recently, angiotensin II (ANG II) chronic treatment, which induces hypertension, was shown to generate nitrosative stress in addition to oxidative stress. We hypothesized that S-nitrosation of sGC occurs in ANG II-induced hypertension, thereby leading to desensitization of sGC to NO hence vascular dysfunction. As expected, ANG II infusion increases blood pressure, aorta remodeling, and protein S-nitrosation. Intravital microscopy indicated that cremaster arterioles are resistant to NO-induced vasodilation in vivo in anesthetized ANG II-treated rats. Concomitantly, NO-induced cGMP production decreases, which correlated with S-nitrosation of sGC in hypertensive rats. This study suggests that S-nitrosation of sGC by ANG II contributes to vascular dysfunction. This was confirmed in vitro by using A7r5 smooth muscle cells infected with adenoviruses expressing sGC or cysteine mutants: ANG II decreases NO-stimulated activity in the wild-type but not in one mutant, C516A. This result indicates that cysteine 516 of sGC mediates ANG II-induced desensitization to NO in cells.

Abstract 019: Vascular Smooth Muscle ADAM17 Contributes To Angiotensin II-induced Abdominal Aortic Aneurysm Formation But Not Hypertension In Mice

Hypertension ◽  
2014 ◽  
Vol 64 (suppl_1) ◽  
Author(s):  
Toshiyuki Tsuji ◽  
Takehiko Takayanagi ◽  
Katherine Elliott ◽  
Takashi Obama ◽  
Kevin Crawford ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Smooth Muscle ◽  
Abdominal Aortic Aneurysm ◽  
Angiotensin Ii ◽  
Aortic Aneurysm ◽  
Vascular Smooth Muscle ◽  
Saline Infusion ◽  
Internal Diameter ◽  
Egfr Activation ◽  
Abdominal Aortic

Enhancement of the renin angiotensin II (AngII) system has been implicated in the development of abdominal aortic aneurysm (AAA). However, detailed molecular mechanism(s) by which AngII promotes AAA remain uncertain. We have demonstrated the critical role of a metalloprotease, ADAM17, in AngII-induced EGFR transactivation and subsequent hypertrophy in vascular smooth muscle cells (VSMC). In caveolin 1-/- mice, AAA formation induced by AngII plus beta-aminopropionitrile (BAPN), a lysyl oxidase inhibitor, was attenuated. The attenuation of AAA formation was associated with suppression of ADAM17 induction and EGFR activation. Others have reported that systemic ADAM17 silencing attenuated CaCl2-induced AAA formation in mice. However, the cell type specific mechanism that is mediating the deleterious effect of ADAM17 in AAA is not well understood. Here, we tested our hypothesis that VSMC ADAM17 activation is required for AngII-promoted AAA formation using ADAM17flox/flox mice bred with sm22a Cre mice. 8 week old mice were co-infused with AngII 1000 ng/kg/min (4w) and BAPN 150 mg/kg/day (2w) or control saline (4w), and AAA formation was evaluated by echo (internal diameter) and measurement (external diameter) of the aortae. In control Cre-/- mice with the co-infusion, 52.4% (11/21) were dead due to aortic rupture/dissection. All surviving Cre-/- mice with co-infusion had AAA with max external/internal diameter (mm) of 2.18±0.55/1.75±0.33 vs 1.01±0.22/1.06±0.02 with saline infusion (p<0.01). In contrast, VSMC ADAM17 deficient Cre+/- with co-infusion did not die or develop AAA. The max external/internal diameter (mm) of AA in Cre+/- with co-infusion was 1.03±0.11/1.05±0.05 vs 1.01±0.12/1.27±0.21 with saline infusion. In contrast, both Cre-/- and +/- mice with the co-infusion developed hypertension assessed by telemetry (MAP mmHg: 161±15 vs 154±12). The ADAM17 deletion was also associated with less EGFR activation, ER/oxidative stress and extravascular fibrosis/matrix deposition. In conclusion, VSMC ADAM17 appears to be a critical metalloprotease contributing to AAA formation but not hypertension induced by AngII + BAPN. The mechanism by which VSMC ADAM17 promotes AAA seems to involve activation of EGFR and induction of ER/oxidative stress.

Abstract 47: Caveolin-1 is Critical for Abdominal Aortic Aneurysm Induced by Angiotensin II

Hypertension ◽  
2013 ◽  
Vol 62 (suppl_1) ◽  
Author(s):  
Takashi Obama ◽  
Takehiko Takayanagi ◽  
Kevin J Crawford ◽  
Tomonori Kobayashi ◽  
Victor Rizzo ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Smooth Muscle ◽  
Abdominal Aortic Aneurysm ◽  
Angiotensin Ii ◽  
Aortic Aneurysm ◽  
Vascular Smooth Muscle Cells ◽  
Critical Role ◽  
Ang Ii ◽  
Caveolin 1 ◽  
Abdominal Aortic

Abdominal aortic aneurysm (AAA) is a significant cause of mortality for adults aged >60 years. Accumulating evidence suggests a role of angiotensin II (Ang II) in abdominal aortic aneurysm (AAA) formation. However, the Ang II-sensitive proximal signaling events primarily responsible for AAA formation remain unclear. We recently reported that caveolin-1 (Cav1) enriched membrane microdomains in vascular smooth muscle cells (VSMC) mediate a metalloprotease ADAM17-dependent EGF receptor (EGFR) transactivation, which is linked to vascular remodeling induced by Ang II. Given that ADAM17 expression is one of the key features in AAA, we have tested our hypothesis that Cav1, a major structural protein of caveolae, plays a critical role for development of AAA by Ang II via regulation of ADAM17. 8 week old male Cav1-/- and the control C57Bl/6 wild-type mice (WT) were co-infused with Ang II (1 μg/kg/min) and β-aminopropionitrile (BAPN: 150mg/kg/day) for 4 weeks to induce AAA. In WT with the co-infusion, 58% (14/24) were dead due to aortic rupture/dissection. All surviving WT with co-infusion had AAA with max diameter (mm) of 2.6±0.18 vs 0.93±0.09 with saline infusion (p<0.01). In contrast, we found that Cav1-/- with co-infusion did not die or develop AAA. The max diameter (mm) of AAA in Cav1-/- with co-infusion was 1.0±0.04 vs 1.1±0.06 with saline infusion (n=7). In contrast, both WT and Cav1-/- with the co-infusion developed hypertension assessed by telemetry (MAP mmHg: 151±5 vs 161±7). We found an increased expression of ADAM17 by IHC and qPCR, and enhanced phosphorylation of EGFR by IHC in WT abdominal aortae with aneurysms. These events were markedly attenuated in Cav1-/- aorta with co-infusion (ADAM17/18S mRNAx10,000 = 3.08±0.71 vs 0.97±0.42 p<0.05, n=4). Furthermore, Cav1-/- aortae showed less ER and oxidative stress compared to WT aortae assessed by IHC. In addition, Cav1 silencing induced by adenovirus encoding Cav1 targeting siRNA embedded miRNA in cultured vascular smooth muscle cells prevented Ang II-induced ADAM17 induction and activation. In conclusion, Cav1 and presumably vascular caveolae microdomains appear to play a critical role in the formation of AAA by Ang II via regulation of the ADAM17/EGFR signaling and subsequent ER/oxidative stress.

scholarly journals Butterfly Pea Flower (Clitoria ternatea Linn.) Extract Ameliorates Cardiovascular Dysfunction and Oxidative Stress in Nitric Oxide-Deficient Hypertensive Rats

Antioxidants ◽  
2021 ◽  
Vol 10 (4) ◽  
pp. 523
Author(s):  
Putcharawipa Maneesai ◽  
Metee Iampanichakul ◽  
Nisita Chaihongsa ◽  
Anuson Poasakate ◽  
Prapassorn Potue ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Nitric Oxide ◽  
Angiotensin Ii ◽  
Vascular Dysfunction ◽  
Renin Angiotensin System ◽  
Left Ventricular ◽  
Sprague Dawley ◽  
Necrosis Factor Alpha ◽  
Clitoria Ternatea ◽  
Plasma Nitrate

In this study, we examine whether Clitoria ternatea Linn. (CT) can prevent Nω-nitro-L-arginine methyl ester hydrochloride (L-NAME)-induced cardiac and vascular dysfunction in rats. Male Sprague Dawley rats were given L-NAME (40 mg/kg, drinking water) and orally administered with CT extract (300 mg/kg/day) or lisinopril (2.5 mg/kg/day) for 5 weeks. The main phytochemical components of the CT extract were found to be flavonoids. The CT extract alleviated the high blood pressure in rats receiving L-NAME. Decreased vasorelaxation responses to acetylcholine and enhanced contractile responses to sympathetic nerve stimulation in aortic rings and mesenteric vascular beds of L-NAME treated rats were ameliorated by CT extract supplementation. Left ventricular hypertrophy and dysfunction were developed in L-NAME rats, which were partially prevented by CT extract treatment. The CT extract alleviated upregulated endothelial nitric oxide synthase expression, decreased plasma nitrate/nitrite levels, and increased oxidative stress in L-NAME rats. It suppressed high levels of serum angiotensin-converting enzyme activity, plasma angiotensin II, and cardiac angiotensin II type 1 receptor, NADPH oxidases 2, nuclear factor-kappa B, and tumor necrosis factor-alpha expression. The CT extract, therefore, partially prevented L-NAME-induced hypertension and cardiovascular alterations in rats. These effects might be related to a reduction in the oxidative stress and renin–angiotensin system activation due to L-NAME in rats.

scholarly journals Ursodeoxycholic Acid Attenuates Acute Aortic Dissection Formation in Angiotensin II-Infused Apolipoprotein E-Deficient Mice Associated with Reduced ROS and Increased Nrf2 Levels

2016 ◽  
Vol 38 (4) ◽  
pp. 1391-1405 ◽  
Author(s):  
Wanjun Liu ◽  
Bei Wang ◽  
Tao Wang ◽  
Xintian Liu ◽  
Xingwei He ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Smooth Muscle ◽  
Angiotensin Ii ◽  
Aortic Dissection ◽  
Ursodeoxycholic Acid ◽  
Acute Aortic Dissection ◽  
Dependent Manner ◽  
Ang Ii

Background/Aims: Acute aortic dissection (AAD) is characterized by excessive smooth muscle cell (SMC) loss, extracellular matrix (ECM) degradation and inflammation. In response to certain stimulations, oxidative stress is activated and regulates apoptosis and inflammation. Excessive apoptosis promotes aortic inflammation and degeneration, leading to AAD formation. This study aimed to clarify role of oxidative stress in the pathogenesis of AAD and whether the antioxidant ursodeoxycholic acid (UDCA) attenuates AAD formation. Methods: Angiotensin II (Ang II) was infused in 8-months male ApoE-/- mice for one week to establish a model of AAD. UDCA (10 mg/kg/day) was administered via intragastric gavage for 3 consecutive days before AngII infusion and also during the AngII infusion for another consecutive 7 days. Results: Ang II-infusion resulted in the incidence of AAD at a rate of 35% (13/37) and UDCA markedly reduced the incidence of AAD to 16% (6/37), accompanied with reduced maximal aortic diameter measured at the suprarenal region of the abdominal aorta. Additionally, UDCA pretreatment prevented Ang II induced generations of reactive oxygen species (ROS) and apoptosis of vascular smooth muscle cells (VSMCs) both in vivo and in. vitro Mechanistically, we found UDCA markedly increased Nrf2 expression in VSMCs and prevented Ang II induced expression of NADPH subunits (p47, p67 and gp91) in Nrf2-dependent manner and rescued the activity of redox enzymes (Cu/Zn-SOD, Mn-SOD and CAT), thereby inhibiting apoptosis of VSMCs. Conclusion: These results demonstrate that UDCA prevented AAD formation by reducing apoptosis of VSMCs caused by oxidative stress in Nrf2 dependent manner and suggest that UDCA might have clinical potential to suppress AAD formation.

scholarly journals Inflammatory Monocytes Determine Endothelial Nitric-oxide Synthase Uncoupling and Nitro-oxidative Stress Induced by Angiotensin II

2014 ◽  
Vol 289 (40) ◽  
pp. 27540-27550 ◽  
Author(s):  
Sabine Kossmann ◽  
Hanhan Hu ◽  
Sebastian Steven ◽  
Tanja Schönfelder ◽  
Daniela Fraccarollo ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Nitric Oxide ◽  
Angiotensin Ii ◽  
Nitric Oxide Synthase ◽  
Endothelial Nitric Oxide Synthase ◽  
Inflammatory Monocytes ◽  
Oxide Synthase ◽  
Endothelial Nitric Oxide

scholarly journals Angiotensin II, Hypercholesterolemia, and Vascular Smooth Muscle Cells: A Perfect Trio for Vascular Pathology

2020 ◽  
Vol 21 (12) ◽  
pp. 4525
Author(s):  
Amanda St. Paul ◽  
Cali B. Corbett ◽  
Rachael Okune ◽  
Michael V. Autieri
Keyword(s):  
Blood Pressure ◽  
Cardiovascular Disease ◽  
Smooth Muscle ◽  
Angiotensin Ii ◽  
Vascular Smooth Muscle ◽  
Vascular Diseases ◽  
Reduce Blood Pressure ◽  
Vascular Pathology ◽  
Lipid Lowering ◽  
Ang Ii

Cardiovascular disease is the leading cause of morbidity and mortality in the Western and developing world, and the incidence of cardiovascular disease is increasing with the longer lifespan afforded by our modern lifestyle. Vascular diseases including coronary heart disease, high blood pressure, and stroke comprise the majority of cardiovascular diseases, and therefore represent a significant medical and socioeconomic burden on our society. It may not be surprising that these conditions overlap and potentiate each other when we consider the many cellular and molecular similarities between them. These intersecting points are manifested in clinical studies in which lipid lowering therapies reduce blood pressure, and anti-hypertensive medications reduce atherosclerotic plaque. At the molecular level, the vascular smooth muscle cell (VSMC) is the target, integrator, and effector cell of both atherogenic and the major effector protein of the hypertensive signal Angiotensin II (Ang II). Together, these signals can potentiate each other and prime the artery and exacerbate hypertension and atherosclerosis. Therefore, VSMCs are the fulcrum in progression of these diseases and, therefore, understanding the effects of atherogenic stimuli and Ang II on the VSMC is key to understanding and treating atherosclerosis and hypertension. In this review, we will examine studies in which hypertension and atherosclerosis intersect on the VSMC, and illustrate common pathways between these two diseases and vascular aging.

scholarly journals Vascular Smooth Muscle Sirtuin‐1 Protects Against Aortic Dissection During Angiotensin II Infusion

2015 ◽  
Vol 29 (S1) ◽  
Author(s):  
Jessica Fry ◽  
Yasunaga Shiraishi ◽  
Yuan Gao ◽  
Robert Weisbrod ◽  
Brandon Maziuk ◽  
...  
Keyword(s):  
Smooth Muscle ◽  
Angiotensin Ii ◽  
Aortic Dissection ◽  
Vascular Smooth Muscle ◽  
Sirtuin 1

scholarly journals Role of oxidative stress in the renal abnormalities induced by experimental hyperuricemia

2008 ◽  
Vol 295 (4) ◽  
pp. F1134-F1141 ◽  
Author(s):  
Laura G. Sánchez-Lozada ◽  
Virgilia Soto ◽  
Edilia Tapia ◽  
Carmen Avila-Casado ◽  
Yuri Y. Sautin ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Nitric Oxide ◽  
Uric Acid ◽  
Angiotensin Ii ◽  
Endothelial Dysfunction ◽  
Systemic Hypertension ◽  
Sprague Dawley ◽  
Renal Vasoconstriction ◽  
Renal Abnormalities ◽  
Oxonic Acid

Endothelial dysfunction is a characteristic feature during the renal damage induced by mild hyperuricemia. The mechanism by which uric acid reduces the bioavailability of intrarenal nitric oxide is not known. We tested the hypothesis that oxidative stress might contribute to the endothelial dysfunction and glomerular hemodynamic changes that occur with hyperuricemia. Hyperuricemia was induced in Sprague-Dawley rats by administration of the uricase inhibitor, oxonic acid (750 mg/kg per day). The superoxide scavenger, tempol (15 mg/kg per day), or placebo was administered simultaneously with the oxonic acid. All groups were evaluated throughout a 5-wk period. Kidneys were fixed by perfusion and afferent arteriole morphology, and tubulointerstitial 3-nitrotyrosine, 4-hydroxynonenal, NOX-4 subunit of renal NADPH-oxidase, and angiotensin II were quantified. Hyperuricemia induced intrarenal oxidative stress, increased expression of NOX-4 and angiotensin II, and decreased nitric oxide bioavailability, systemic hypertension, renal vasoconstriction, and afferent arteriolopathy. Tempol treatment reversed the systemic and renal alterations induced by hyperuricemia despite equivalent hyperuricemia. Moreover, because tempol prevented the development of preglomerular damage and decreased blood pressure, glomerular pressure was maintained at normal values as well. Mild hyperuricemia induced by uricase inhibition causes intrarenal oxidative stress, which contributes to the development of the systemic hypertension and the renal abnormalities induced by increased uric acid. Scavenging of the superoxide anion in this setting attenuates the adverse effects induced by hyperuricemia.

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