Abstract P231: Inhibition of Mir-762 Prevents and Reverses Ang II Induced Aortic Stiffening

Hypertension ◽  
2016 ◽  
Vol 68 (suppl_1) ◽  
Author(s):  
Kim Ramil C Montaniel ◽  
Jing Wu ◽  
Matthew R Bersi ◽  
Liang Xiao ◽  
Hana A Itani ◽  
...  
Keyword(s):  
P38 Mapk ◽  
Aortic Stiffness ◽  
Fold Increase ◽  
Organ Damage ◽  
Locked Nucleic Acid ◽  
Ang Ii ◽  
New Approach ◽  
Acid Inhibitor ◽  
Aortic Stiffening

We and others have shown that hypertension (HTN) is linked with striking fibrosis in the aortic adventitia. This leads to aortic stiffening, leading to organ damage. Through a screen of microRNAs (miRNAs) in the aorta, we found that miR-762 is the most upregulated miRNA in Ang II hypertensive mice. qRT-PCR confirmed that miR-762 is upregulated 6.35±1.22 (p=0.03) fold in Ang II-infused mice compared to controls. To study the role of miR-762 in HTN, we administered a locked nucleic acid inhibitor of miR-762. MiR-762 inhibition normalized stress-strain relationships and aortic systolic energy storage (ASE) (Table). Moreover, miR-762 inhibition in the last 2 weeks of Ang II infusion reversed aortic stiffness in mice treated with 4 wk of Ang II (ASE, 4 wk Ang II [51±5.18 kPa] vs 4wk Ang II + LNA-762 (last 2 wk) [20±1.76 kPa], p<0.0001). Further studies showed that miR-762 inhibition reduced mRNA for several collagens and fibronectin and upregulated collagenases MMP1a, 8 and 13 (Table). Lastly, we found that miR-762 inhibition during Ang II infusion led to a 9.11±1.92 (p=0.007) fold increase in Sprouty1 mRNA, suggesting that miR-762 targets Sprouty1 mRNA. Sprouty1 inhibits the activation of p38-MAPK which is critical in the process of aortic stiffening. Hence, miR-762 modulates aortic stiffening and fibrosis through a Sprouty1-p38-MAPK mechanism. Thus, miR-762 has a major role in modulating aortic stiffening and its inhibition dramatically inhibits pathological fibrosis, enhances matrix degradation, prevents and reverses aortic stiffness. miR-762 inhibition might represent a new approach to prevent aortic stiffening and its consequent end-organ damage.

Abstract 7: AntagomiR-762 Prevents and Reverses Angiotensin II Induced Aortic Stiffening

2016 ◽  
Vol 36 (suppl_1) ◽  
Author(s):  
Kim Ramil C Montaniel ◽  
Jing Wu ◽  
Matthew R Bersi ◽  
Liang Xiao ◽  
Hana A Itani ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Aortic Stiffness ◽  
Organ Damage ◽  
Locked Nucleic Acid ◽  
Ang Ii ◽  
New Approach ◽  
End Organ Damage ◽  
Acid Inhibitor ◽  
Aortic Stiffening

We and others have shown that hypertension (HTN) is associated with a striking deposition of collagen in the aortic adventitia. This leads to aortic stiffening, eventually leading to end-organ damage. Through a screen of microRNAs (miRNAs) in the aorta, 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 Ang II-infused mice compared to 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 influence the hypertensive response to Ang II, yet it normalized stress-strain relationships and aortic systolic energy storage (ASE) (Table). Moreover, antagomiR-762 administration in the last 2 weeks of Ang II infusion reversed aortic stiffness in mice treated with Ang II for 4 weeks (ASE, 4 wk Ang II [51±5.18 kPa] vs 4wk Ang II + antagomiR-762(last two weeks) [20±1.76 kPa], p<0.0001). Further studies showed that antagomiR-762 reduced mRNA for several collagens and fibronectin and dramatically upregulated collagenases MMP1a, 8 and 13 (Table). Hence, miR-762 plays a major role in modulating aortic stiffening and its inhibition dramatically inhibits pathological fibrosis, enhances matrix degradation, prevents and reverses aortic stiffness. AntagomiR-762 might represent a new approach to prevent and possibly reverse aortic stiffening and its consequent end-organ damage.

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.

Abstract P618: Inactivation of Mitochondrial Deacetylase Sirt3 Promotes Vascular Oxidative Stress, Increases Endothelial Dysfunction and Exacerbates Hypertension

Hypertension ◽  
2016 ◽  
Vol 68 (suppl_1) ◽  
Author(s):  
Anna E Dikalova ◽  
Roman Uzhachenko ◽  
Hana A Itani ◽  
David G Harrison ◽  
Sergey Dikalov
Keyword(s):  
Oxidative Stress ◽  
Smooth Muscle ◽  
Endothelial Dysfunction ◽  
Ex Vivo ◽  
Fold Increase ◽  
Organ Damage ◽  
Ang Ii ◽  
Wild Type ◽  
Vascular Oxidative Stress

Endothelial dysfunction is associated with aging, diabetes, hyperlipidemia, obesity and these risk factors affect the expression and activity of the mitochondrial deacetylase Sirt3. Sirt3 activates major antioxidant SOD2 by deacetylation of specific lysine residues and Sirt3 depletion increases oxidative stress. We hypothesized that loss of vascular Sirt3 increases endothelial dysfunction, promotes hypertension and end organ damage. The role of vascular Sirt3 was studied in wild-type C57Bl/6J mice and tamoxifen-inducible smooth muscle specific Sirt3 knockout mice (Smc Sirt3 KO ) using angiotensin II model of hypertension (Ang II, 0.7 mg/kg/day). Western blot showed 30% reduction of vascular Sirt3 and 2-fold increase in SOD2 acetylation in Ang II-infused WT mice. We have tested if ex vivo treatment of aorta with Sirt3 activator resveratrol improves endothelial function. Indeed, ex vivo incubation with resveratrol (10 μM) significantly reduced SOD2 acetylation, diminished mitochondrial O 2 and increased endothelial NO to normal level while Sirt3-inactive analog dihydroresveratrol had no effect. Specific role of vascular Sirt3 was studied in Smc Sirt3 KO mice by crossing floxed Sirt3 mice with mice carrying gene for inducible cre in the vascular smooth muscle. Sirt3 deletion exacerbates hypertension (165 mm Hg vs 155 mm Hg in wild-type) and significantly increases mortality in Ang II-infused Smc Sirt3 KO mice (60% vs 10% in wild-type) associated with severe edema and aortic aneurysm (100% vs 20% in wild-type). Decrease of NO is a hallmark of endothelial dysfunction in hypertension due to vascular oxidative stress. Indeed, Ang II infusion increased vascular O 2 by 2-fold and reduced endothelial NO by 2-fold. Interestingly, Ang II infusion in Smc Sirt3 KO mice caused severe vascular oxidative stress (3-fold increase in O 2 ) and exacerbated endothelial dysfunction (4-fold decrease in NO). These data indicate that reduced vascular Sirt3 activity occurs in hypertension and this promotes vascular oxidative stress, increases endothelial dysfunction, exacerbates hypertension, increases end-organ-damage and mortality. It is conceivable that Sirt3 agonists and SOD2 mimetics may have therapeutic potential in cardiovascular disease.

Dissociation in plasma renin and adrenal ANG II and aldosterone responses to sodium restriction in rats

1991 ◽  
Vol 261 (4) ◽  
pp. E487-E494 ◽  
Author(s):  
A. Menachery ◽  
L. M. Braley ◽  
I. Kifor ◽  
R. Gleason ◽  
G. H. Williams
Keyword(s):  
Plasma Renin ◽  
Fold Increase ◽  
Plasma Aldosterone ◽  
Delayed Response ◽  
Ang Ii ◽  
Sodium Restriction ◽  
Sodium Depletion ◽  
Pathway Activity

In rats, plasma renin activity (PRA) increases sharply, reaching a plateau within hours of sodium restriction. Plasma aldosterone increases gradually, not reaching a plateau for 1-2 days. To determine whether this dissociation is secondary to the time needed to modify adrenal sensitivity to angiotensin II (ANG II) and to assess the role of locally produced ANG II in this process, rats were salt restricted for 0-120 h. Plasma hormone levels were assessed, adrenal ANG II was measured, and basal and ANG II (1 x 10(-8) M)-stimulated steroidogenesis were determined in vitro. Although PRA attained an elevated plateau within 8 h, plasma aldosterone did not peak until after 48 h of sodium depletion. The in vitro aldosterone sensitivity to exogenous ANG II was not apparent until rats had been salt restricted for 16 h. A plateau (4-fold increase above the ANG II response on high salt) was achieved between 24 and 48 h. Adrenal ANG II also exhibited a similar delayed response that correlates significantly with changes in aldosterone biosynthesis and late pathway activity. Thus the dissociation between PRA and plasma aldosterone may be secondary to a lag in the zona glomerulosa's (ZG) steroidogenic response to ANG II as well as a parallel lag in tissue ANG II production, suggesting that changes in tissue ANG II may mediate ZG sensitivity to ANG II during sodium deprivation.

Cardiac hypertrophy is associated with altered thioredoxin and ASK-1 signaling in a mouse model of menopause

2008 ◽  
Vol 295 (4) ◽  
pp. H1481-H1488 ◽  
Author(s):  
Talin Ebrahimian ◽  
M. Ram Sairam ◽  
Ernesto L. Schiffrin ◽  
Rhian M. Touyz
Keyword(s):  
Oxidative Stress ◽  
Cardiac Hypertrophy ◽  
Target Organ Damage ◽  
Organ Damage ◽  
Receptor Expression ◽  
Ang Ii ◽  
Antioxidant Function ◽  
Endogenous Antioxidant

Oxidative stress is implicated in menopause-associated hypertension and cardiovascular disease. The role of antioxidants in this process is unclear. We questioned whether the downregulation of thioredoxin (TRX) is associated with oxidative stress and the development of hypertension and target-organ damage (cardiac hypertrophy) in a menopause model. TRX is an endogenous antioxidant that also interacts with signaling molecules, such as apoptosis signal-regulated kinase 1 (ASK-1), independently of its antioxidant function. Aged female wild-type (WT) and follitropin receptor knockout (FORKO) mice (20–24 wk), with hormonal imbalances, were studied. Mice were infused with ANG II (400 ng·kg−1·min−1; 14 days). Systolic blood pressure was increased by ANG II in WT (166 ± 8 vs. 121 ± 5 mmHg) and FORKO (176 ± 7 vs. 115 ± 5 mmHg; P < 0.0001; n = 9/group) mice. In ANG II-infused FORKO mice, cardiac mass was increased by 42% ( P < 0.001). This was associated with increased collagen content and augmented ERK1/2 phosphorylation (2-fold). Cardiac TRX expression and activity were decreased by ANG II in FORKO but not in WT ( P < 0.01) mice. ASK-1 expression, cleaved caspase III content, and Bax/Bcl-2 content were increased in ANG II-infused FORKO ( P < 0.05). ANG II had no effect on cardiac NAD(P)H oxidase activity or on O2•− levels in WT or FORKO. Cardiac ANG II type 1 receptor expression was similar in FORKO and WT. These findings indicate that in female FORKO, ANG II-induced cardiac hypertrophy and fibrosis are associated with the TRX downregulation and upregulation of ASK-1/caspase signaling. Our data suggest that in a model of menopause, protective actions of TRX may be blunted, which could contribute to cardiac remodeling independently of oxidative stress and hypertension.

scholarly journals Endothelial-derived extracellular microRNA-92a promotes arterial stiffness by regulating phenotype changes of vascular smooth muscle cells

2022 ◽  
Vol 12 (1) ◽  
Author(s):  
Chen Wang ◽  
Haoyu Wu ◽  
Yuanming Xing ◽  
Yulan Ye ◽  
Fangzhou He ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Smooth Muscle ◽  
Arterial Stiffness ◽  
Vascular Smooth Muscle ◽  
Vascular Endothelial Cells ◽  
Locked Nucleic Acid ◽  
Vascular Endothelial ◽  
Ang Ii

AbstractEndothelial dysfunction and vascular smooth muscle cell (VSMC) plasticity are critically involved in the pathogenesis of hypertension and arterial stiffness. MicroRNAs can mediate the cellular communication between vascular endothelial cells (ECs) and neighboring cells. Here, we investigated the role of endothelial-derived extracellular microRNA-92a (miR-92a) in promoting arterial stiffness by regulating EC–VSMC communication. Serum miR-92a level was higher in hypertensive patients than controls. Circulating miR-92a level was positively correlated with pulse wave velocity (PWV), systolic blood pressure (SBP), diastolic blood pressure (DBP), and serum endothelin-1 (ET-1) level, but inversely with serum nitric oxide (NO) level. In vitro, angiotensin II (Ang II)-increased miR-92a level in ECs mediated a contractile-to-synthetic phenotype change of co-cultured VSMCs. In Ang II-infused mice, locked nucleic acid-modified antisense miR-92a (LNA-miR-92a) ameliorated PWV, SBP, DBP, and impaired vasodilation induced by Ang II. LNA-miR-92a administration also reversed the increased levels of proliferative genes and decreased levels of contractile genes induced by Ang II in mouse aortas. Circulating serum miR-92a level and PWV were correlated in these mice. These findings indicate that EC miR-92a may be transported to VSMCs via extracellular vesicles to regulate phenotype changes of VSMCs, leading to arterial stiffness.

Abstract 139: Loss of Thymosin b4 Exacerbates Renal and Cardiac Damage in Angiotensin-II Hypertension

Hypertension ◽  
2017 ◽  
Vol 70 (suppl_1) ◽  
Author(s):  
Nitin Kumar ◽  
Tang-Dong Liao ◽  
Cesar Romero ◽  
Mani Maheshwari ◽  
Ed Peterson ◽  
...  
Keyword(s):  
Angiotensin Ii ◽  
Tissue Damage ◽  
Cardiac Fibrosis ◽  
Organ Damage ◽  
Protective Role ◽  
High Expression ◽  
Ang Ii ◽  
Cardiac Damage ◽  
Filtration Barrier

Angiotensin-II (Ang-II)-induced hypertension is associated with tissue damage and fibrosis in the kidney and heart. Thymosin β4 (Tβ4) regulates cell morphology, inflammation and fibrosis in several organs and administration of exogenous Tβ4 is protective in diabetic nephropathy and unilateral ureteral obstruction model. However, role of endogenous Tβ4 in hypertension-induced organ damage is unknown. We hypothesize that, loss of Tβ4 accelerates renal and cardiac fibrosis and damage in Ang-II hypertension. To test our hypothesis, Tβ4 knockout (Tβ4 -/- ) and wild-type (Tβ4 +/+ ) C57BL/6 mice (n=6-10) were infused continuously for six-weeks with either Ang-II (980 ng/kg/min) or vehicle via osmotic minipumps. All the results are presented in table 1. In Ang-II infusion, systolic blood-pressure were not different between both strains (Table 1). Interestingly, urinary albuminuria was significantly higher in Tβ4 -/- mice compared to Tβ4 +/+ mice by Ang-II. High expression of Tβ4 is found in the glomeruli along with high expression of Nephrin, an important protein in the filtration barrier of the kidney. In Ang-II infusion, nephrin protein expression was greatly reduced in mice deficient of Tβ4, suggesting that loss of nephrin is one of the mechanism for elevated urinary albumin in Tβ4 -/- mice. Additionally, renal fibrosis was higher in Tβ4 -/- mice. We also studied cardiac damage and observed that in Ang-II infusion, cardiac hypertrophy and cardiac fibrosis were much higher in Tβ4 -/- mice. These data indicate that loss of endogenous Tβ4 caused significant tissue damage in the kidney and heart in Ang-II hypertension, suggesting renal and cardiac protective role of this peptide.

Role of asymmetric dimethylarginine for angiotensin II-induced target organ damage in mice

2008 ◽  
Vol 294 (2) ◽  
pp. H1058-H1066 ◽  
Author(s):  
Johannes Jacobi ◽  
Renke Maas ◽  
Nada Cordasic ◽  
Kilian Koch ◽  
Roland E. Schmieder ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Blood Pressure ◽  
Asymmetric Dimethylarginine ◽  
Interstitial Fibrosis ◽  
Target Organ Damage ◽  
Organ Damage ◽  
Target Organ ◽  
Ang Ii ◽  
Renal Interstitial Fibrosis

The aim of the present study was to investigate the role of the endogenous nitric oxide synthase inhibitor asymmetric dimethylarginine (ADMA) and its degrading enzyme dimethylarginine dimethylaminohydrolase (DDAH) in angiotensin II (ANG II)-induced hypertension and target organ damage in mice. Mice transgenic for the human DDAH1 gene (TG) and wild-type (WT) mice (each, n = 28) were treated with 1.0 μg·kg−1·min−1 ANG II, 3.0 μg·kg−1·min−1 ANG II, or phosphate-buffered saline over 4 wk via osmotic minipumps. Blood pressure, as measured by tail cuff, was elevated to the same degree in TG and WT mice. Plasma levels of ADMA were lower in TG than WT mice and were not affected after 4 wk by either dose of ANG II in both TG and WT animals. Oxidative stress within the wall of the aorta, measured by fluorescence microscopy using the dye dihydroethidium, was significantly reduced in TG mice. ANG II-induced glomerulosclerosis was similar between WT and TG mice, whereas renal interstitial fibrosis was significantly reduced in TG compared with WT animals. Renal mRNA expression of protein arginine methyltransferase (PRMT)1 and DDAH2 increased during the infusion of ANG II, whereas PRMT3 and endogenous mouse DDAH1 expression remained unaltered. Chronic infusion of ANG II in mice has no effect on the plasma levels of ADMA after 4 wk. However, an overexpression of DDAH1 alleviates ANG II-induced renal interstitial fibrosis and vascular oxidative stress, suggesting a blood pressure-independent effect of ADMA on ANG II-induced target organ damage.

Abstract P274: Inhibition Of Abnormal Exosome Release Prevents Excessive Aortic Stiffness And Relaxation Dysfunction In Diet-induced Obesity

Hypertension ◽  
2021 ◽  
Vol 78 (Suppl_1) ◽  
Author(s):  
Javad Habibi ◽  
Vincent G DeMarco ◽  
Dongqing Chen ◽  
Jack L. Hulse ◽  
Adam Whaley-connell ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Aortic Stiffness ◽  
Blood Pressure Measurement ◽  
Cell Communication ◽  
Cell Types ◽  
Vascular Relaxation ◽  
Diet Induced Obesity ◽  
Diastolic Relaxation ◽  
Aortic Stiffening

Interactions between over-nutrition and abnormal exosome release impact insulin sensitivity and the development of cardiovascular disease (CVD). Recent data have shown that exosomes can be released from various cell types, including adipocytes and vascular cells, and that they exist in body fluids and tissues functioning as mediators of cell-cell communication. However, the specific role of exosomes in diet-induced excessive vascular stiffness and hypertension has not been explored. Accordingly, we hypothesized that abnormal release of exosomes contributes to western diet (WD)- induced aortic stiffening and impaired vascular diastolic relaxation. We further posited that GW4869, an antagonist of neutral sphingomyelinase 2 (nSMase2) which promotes exosome production and release, would prevent WD-induced aortic stiffening and impaired vascular relaxation. Six week-old female C57BL/6L mice were fed a mouse chow (CD) or WD containing excess fat (46%) and fructose (17.5%) for 16 weeks with or without GW4849. To this point, 200 μl of 0.3 mg/mL GW4869 in 0.9% normal saline (60 μg/mouse; 2-2.5 μg/g body weight) was injected intraperitoneally every 48 hours for 12 weeks. 16 weeks of WD induced an increase of aortic stiffness as examined by pulse wave velocity (PWV) and impaired the aortic vasodilation responses to acetylcholine (Ach) and sodium nitroprusside (SNP) (10 -9 -10 -4 mol/L). However, GW4869 treatment prevented the WD-induced excessive aortic stiffness, as well as impairment of endothelium dependent/independent vascular relaxation. There were no significant differences in blood pressure between each group examined by tail cuff blood pressure measurement. These findings support the hypothesis that abnormal release of exosomes play an important role in WD-induced excessive aortic stiffness, impaired vascular relaxation and CVD in diet-induced obesity.

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