Endothelial Nitric Oxide Is Not Involved in Circadian Rhythm Generation of Blood Pressure: Experiments in Wild‐Type C57 and eNOS Knock‐Out Mice under Light‐Dark and Free‐Run Conditions

2007 ◽  
Vol 24 (6) ◽  
pp. 1231-1240 ◽  
Author(s):  
M. Arraj ◽  
B. Lemmer
Keyword(s):  
Nitric Oxide ◽  
Blood Pressure ◽  
Circadian Rhythm ◽  
Rhythm Generation ◽  
Wild Type ◽  
Knock Out ◽  
Knock Out Mice ◽  
Endothelial Nitric Oxide

Abstract 347: eNOS Deficiency Ameliorates Vascular Remodeling Induced by Periadventitial Injury in SOD1 Knock-Out Mice

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Keiichiro Kataoka ◽  
Masaya Fukuda ◽  
Eiichiro Yamamoto ◽  
Taishi Nakamura ◽  
Hisao Ogawa ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Vascular Remodeling ◽  
List Type ◽  
Neointimal Formation ◽  
Knock Out ◽  
Copper Zinc ◽  
Knock Out Mice ◽  
Oxide Synthase ◽  
Endothelial Nitric Oxide ◽  
Deficient Mice

Background: Copper/zinc SOD (SOD1) is a major enzyme which deactivates superoxide radicals (O2−), and endothelial nitric oxide synthase (eNOS) synthesizes nitric oxide (NO) in endothelial cells. Reduction of each enzyme can increase oxidative stress, leading to cardiovascular dysfunction. Herein, we established SOD1 and eNOS double deficient mice, and examined their physiological and pathological cardiovascular phenotypes to clarify the function of eNOS in cardiovascular system in the case of SOD1 deficiency. Methods and Results: SOD1 deficient mice (SOD-KO) were crossbred with eNOS deficient mice (eNOS-KO), and SOD1 and eNOS double-deficient mice (Do-KO) were established. Do-KO had significantly higher blood pressure (BP) than SOD-KO (129.6 ± 4.7 vs. 102.1 ± 1.2 mmHg, p<0.0001). Do-KO had significantly higher heart weights than SOD-KO (3.12 ± 0.09 vs. 2.89 ± 0.03 mg/g, p<0.01). Relaxation of carotid arteries due to acetylcholine was mildly impaired in SOD-KO when compared with wild type mice (WT), while relaxation to acetylcholine was completely ablated in Do-KO. These data indicated that targeted ablation of eNOS in SOD-KO impaired their vascular relaxation, and caused hypertension. Next, we examined vascular remodeling induced by periadventitial cuff-injuries. Four weeks after cuff replacement, marked neointimal formation was induced in SOD-KO; however, eNOS deficiency in SOD-KO ameliorated the vascular remodeling of SOD-KO, and significantly decreased the ratio of intimal to medial areas (1.23 ± 0.23 vs. 2.23 ± 0.38, p<0.05). This data shows that eNOS enhances the vascular remodeling of SOD-KO caused by cuff injury. NO and O2− react to form the strong oxidant peroxynitrite, which is involved in vascular injury. The levels of 3-nitrotyrosine, a marker of peroxynitrite generation, were significantly elevated in the injured arteries of SOD-KO, while their elevation were attenuated in Do-KO. This indicates that NO derived from eNOS enhances the peroxynitrite formation in injured arteries of SOD-KO, so that vascular remodeling may be markedly enhanced. Conclusion: Our results demonstrate that peroxynitrite, generated from O2− and eNOS derived-NO, plays a key role in vascular remodeling induced by periadventitial injury.

Abstract P345: Overexpression of Mitochondrial Deacetylase Sirt3 Protects Endothelial Function and Attenuates Hypertension While Sirt3 Depletion Increases Oxidative Stress and Endothelial Dysfunction Due to SOD2 Hyperacetylation

Hypertension ◽  
2017 ◽  
Vol 70 (suppl_1) ◽  
Author(s):  
Anna E Dikalova ◽  
Hana A Itani ◽  
Arvind K Pandey ◽  
David G Harrison ◽  
Sergey I Dikalov
Keyword(s):  
Nitric Oxide ◽  
Blood Pressure ◽  
Smooth Muscle ◽  
Angiotensin Ii ◽  
Endothelial Dysfunction ◽  
Endothelial Function ◽  
Knockout Mice ◽  
Whole Body ◽  
Wild Type ◽  
Endothelial Nitric Oxide

We have recently reported SOD2 hyperacetylation and reduced Sirt3 level in human subjects with essential hypertension. We hypothesized that diminished Sirt3 expression promotes endothelial dysfunction and hypertension while Sirt3 overexpression protects endothelial function and attenuates hypertension. Indeed, hypertension was markedly increased in Sirt3 knockout (Sirt3 -/- ) in response to angiotensin II (0.7 mg/kg/day) compared with wild-type C57Bl/6J mice. Sirt3 depletion caused SOD2 inactivation due to SOD2 hyperacetylation, increased mitochondrial O 2 • and diminished endothelial nitric oxide. Angiotensin II infusion in wild-type mice was associated with Sirt3 inactivation and SOD2 hyperacetylation in aorta and kidney. To test the specific role of Sirt3 in vasculature we have generated tamoxifen-inducible endothelium specific Sirt3 knockout mice (Ec Sirt3 KO ) and tamoxifen-inducible smooth muscle specific Sirt3 knockout mice (Smc Sirt3 KO ). Deletion of Sirt3 in smooth muscle exacerbated hypertension (165 mm Hg vs 155 mm Hg in wild-type) and significantly increased mortality in angiotensin II infused Smc Sirt3 KO mice (30% vs 3% in wild-type) which was associated with higher rate of aortic aneurysm. Ec Sirt3 KO mice had elevated basal blood pressure by 12 mm Hg and hypertension was exacerbated in Ec Sirt3 KO mice accompanied by impaired vascular relaxation and reduced endothelial nitric oxide. Treatment of angiotensin II-infused Sirt3 -/- mice with SOD2 mimetic mitoTEMPO rescued endothelial-dependent relaxation and reduced blood pressure. We tested if Sirt3 overexpression protects endothelial function and attenuates angiotensin II-induced hypertension. These new mice were obtained by crossing the EIIa-cre with Sirt3flox mice resulting in constitutively increased Sirt3 in the whole body. Sirt3 overexpression abolished angiotensin II induced impairment of vasorelaxation and attenuated development of hypertension. Our data suggest that diminished Sirt3 activity leads to SOD2 hyperacetylation and contributes to the pathogenesis of hypertension. It is conceivable that Sirt3 agonists and SOD2 mimetics may have therapeutic potential in cardiovascular disease.

Indispensable role of endothelial nitric oxide synthase in caloric restriction-induced cardioprotection against ischemia-reperfusion injury

2015 ◽  
Vol 308 (8) ◽  
pp. H894-H903 ◽  
Author(s):  
Ken Shinmura ◽  
Kayoko Tamaki ◽  
Kentaro Ito ◽  
Xiaoxiang Yan ◽  
Tsunehisa Yamamoto ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Blood Pressure ◽  
Reperfusion Injury ◽  
Caloric Restriction ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Left Ventricular ◽  
Sirtuin 1 ◽  
Wild Type ◽  
Endothelial Nitric Oxide

Caloric restriction (CR) confers cardioprotection against ischemia-reperfusion injury (IRI). We previously found that treatment with NG-nitro-l-arginine methyl ester completely abrogates CR-induced cardioprotection and increases nuclear sirtuin 1 (Sirt1) expression. However, it remains unclear whether endothelial nitric oxide (NO) synthase (eNOS) plays a role in CR-induced cardioprotection and Sirt1 activation. We subjected eNOS-deficient (eNOS−/−) mice to either 3-mo ad libitum (AL) feeding or CR (−40%). Isolated perfused hearts were subjected to 25-min global ischemia followed by 60-min reperfusion. The degree of myocardial IRI in AL-fed eNOS−/− mice was more severe than that in AL-fed wild-type mice. Furthermore, CR did not exert cardioprotection in eNOS−/− mice. eNOS−/− mice exhibited elevated blood pressure and left ventricular hypertrophy compared with wild-type mice, although they underwent CR. Although nuclear Sir1 content was increased, the increases in cardiac Sirt1 activity with CR was absent in eNOS−/− mice. In eNOS−/− mice treated with hydralazine, blood pressure and left ventricular weight became comparable with CR-treated wild-type mice. However, CR-induced cardioprotection was not observed. Resveratrol enhanced cardiac Sirt1 activity but failed to mimic CR-induced cardioprotection in eNOS−/− mice. Finally, combination therapy with resveratrol and hydralazine attenuated myocardial IRI and reduced infarct size in eNOS−/− mice, and their effects were comparable with those observed in CR-treated wild-type mice. These results demonstrate the essential roles of eNOS in the development of CR-induced cardioprotection and Sirt1 activation during CR. The combination of a relatively low dose of resveratrol with an adequate vasodilator therapy might be useful for managing patients with endothelial dysfunction associated with impaired NO bioavailability.

Functional characterization of the H+/K+ ATPase in wild type and gastrin knock-out mice

2007 ◽  
Vol 45 (05) ◽  
Author(s):  
A Schnur ◽  
P Hegyi ◽  
V Venglovecz ◽  
Z Rakonczay ◽  
I Ignáth ◽  
...  
Keyword(s):  
Functional Characterization ◽  
Wild Type ◽  
Knock Out ◽  
Knock Out Mice

Neuregulin-1 Compensates for Endothelial Nitric Oxide Synthase Deficiency

2021 ◽  
Author(s):  
Hadis Shakeri ◽  
Jente R.A. Boen ◽  
Sofie De Moudt ◽  
Jhana O. Hendrickx ◽  
Arthur J.A. Leloup ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Cardiac Fibrosis ◽  
Separate Experiment ◽  
No Production ◽  
Ang Ii ◽  
Wild Type ◽  
Paracrine Factor ◽  
Renal Hypertrophy ◽  
Neuregulin 1 ◽  
Endothelial Nitric Oxide

Endothelial cells (ECs) secrete different paracrine signals that modulate the function of adjacent cells; two examples of these paracrine signals are nitric oxide (NO) and neuregulin-1 (NRG1), a cardioprotective growth factor. Currently, it is undetermined whether one paracrine factor can compensate for the loss of another. Herein, we hypothesized that NRG1 can compensate for endothelial NO synthase (eNOS) deficiency. Methods. We characterized eNOS null and wild type (WT) mice by cardiac ultrasound and histology and we determined circulating NRG1 levels. In a separate experiment, 8 groups of mice were divided into 4 groups of eNOS null mice and wild type (WT) mice; half of the mice received angiotensin II (Ang II) to induce a more severe phenotype. Mice were randomized to daily injections with NRG1 or vehicle for 28 days. Results. eNOS deficiency increased NRG1 plasma levels, indicating that ECs increase their NRG1 expression when NO production is deleted. eNOS deficiency also increased blood pressure, lowered heart rate, induced cardiac fibrosis, and affected diastolic function. In eNOS null mice, Ang II administration increased cardiac fibrosis, but also induced cardiac hypertrophy and renal fibrosis. NRG1 administration prevented the cardiac and renal hypertrophy and fibrosis caused by Ang II infusion and eNOS deficiency. Moreover, Nrg1 expression in the myocardium is shown to be regulated by miR-134. Conclusion. This study indicates that administration of endothelium-derived NRG1 can compensate for eNOS deficiency in the heart and kidneys.

Sign in / Sign up

Export Citation Format

Share Document