Therapeutic Potential of Phosphodiesterase Inhibitors for Endothelial Dysfunction- Related Diseases

2020 ◽  
Vol 26 (30) ◽  
pp. 3633-3651 ◽  
Author(s):  
Javier Blanco-Rivero ◽  
Fabiano E. Xavier
Keyword(s):  
Nitric Oxide ◽  
Endothelial Dysfunction ◽  
Endothelial Function ◽  
Therapeutic Potential ◽  
Treatment Strategies ◽  
Phosphodiesterase Inhibitors ◽  
Developed Countries ◽  
Major Health Problem ◽  
Pde Inhibitors ◽  
Pharmaceutical Industries

Cardiovascular diseases (CVD) are considered a major health problem worldwide, being the main cause of mortality in developing and developed countries. Endothelial dysfunction, characterized by a decline in nitric oxide production and/or bioavailability, increased oxidative stress, decreased prostacyclin levels, and a reduction of endothelium-derived hyperpolarizing factor is considered an important prognostic indicator of various CVD. Changes in cyclic nucleotides production and/ or signalling, such as guanosine 3', 5'-monophosphate (cGMP) and adenosine 3', 5'-monophosphate (cAMP), also accompany many vascular disorders that course with altered endothelial function. Phosphodiesterases (PDE) are metallophosphohydrolases that catalyse cAMP and cGMP hydrolysis, thereby terminating the cyclic nucleotide-dependent signalling. The development of drugs that selectively block the activity of specific PDE families remains of great interest to the research, clinical and pharmaceutical industries. In the present review, we will discuss the effects of PDE inhibitors on CVD related to altered endothelial function, such as atherosclerosis, diabetes mellitus, arterial hypertension, stroke, aging and cirrhosis. Multiple evidences suggest that PDEs inhibition represents an attractive medical approach for the treatment of endothelial dysfunction-related diseases. Selective PDE inhibitors, especially PDE3 and PDE5 inhibitors are proposed to increase vascular NO levels by increasing antioxidant status or endothelial nitric oxide synthase expression and activation and to improve the morphological architecture of the endothelial surface. Thereby, selective PDE inhibitors can improve the endothelial function in various CVD, increasing the evidence that these drugs are potential treatment strategies for vascular dysfunction and reinforcing their potential role as an adjuvant in the pharmacotherapy of CVD.

Tackling endothelial dysfunction by modulating NOS uncoupling: new insights into its pathogenesis and therapeutic possibilities

2012 ◽  
Vol 302 (5) ◽  
pp. E481-E495 ◽  
Author(s):  
Rinrada Kietadisorn ◽  
Rio P. Juni ◽  
An L. Moens
Keyword(s):  
Nitric Oxide ◽  
Endothelial Dysfunction ◽  
Endothelial Function ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Therapeutic Interventions ◽  
Enos Uncoupling ◽  
Underlying Causes ◽  
Oxide Synthase ◽  
Endothelial Nitric Oxide

Endothelial nitric oxide synthase (eNOS) serves as a critical enzyme in maintaining vascular pressure by producing nitric oxide (NO); hence, it has a crucial role in the regulation of endothelial function. The bioavailability of eNOS-derived NO is crucial for this function and might be affected at multiple levels. Uncoupling of eNOS, with subsequently less NO and more superoxide generation, is one of the major underlying causes of endothelial dysfunction found in atherosclerosis, diabetes, hypertension, cigarette smoking, hyperhomocysteinemia, and ischemia/reperfusion injury. Therefore, modulating eNOS uncoupling by stabilizing eNOS activity, enhancing its substrate, cofactors, and transcription, and reversing uncoupled eNOS are attractive therapeutic approaches to improve endothelial function. This review provides an extensive overview of the important role of eNOS uncoupling in the pathogenesis of endothelial dysfunction and the potential therapeutic interventions to modulate eNOS for tackling endothelial dysfunction.

scholarly journals Arginase inhibition restores NOS coupling and reverses endothelial dysfunction and vascular stiffness in old rats

2009 ◽  
Vol 107 (4) ◽  
pp. 1249-1257 ◽  
Author(s):  
Jae Hyung Kim ◽  
Lukasz J. Bugaj ◽  
Young Jun Oh ◽  
Trinity J. Bivalacqua ◽  
Sungwoo Ryoo ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Endothelial Dysfunction ◽  
Endothelial Function ◽  
Vascular Stiffness ◽  
Arginase Activity ◽  
Young Rats ◽  
Arginase 1 ◽  
Enos Uncoupling ◽  
Old Rats

There is increasing evidence that upregulation of arginase contributes to impaired endothelial function in aging. In this study, we demonstrate that arginase upregulation leads to endothelial nitric oxide synthase (eNOS) uncoupling and that in vivo chronic inhibition of arginase restores nitroso-redox balance, improves endothelial function, and increases vascular compliance in old rats. Arginase activity in old rats was significantly increased compared with that shown in young rats. Old rats had significantly lower nitric oxide (NO) and higher superoxide (O2−) production than young. Acute inhibition of both NOS, with NG-nitro-l-arginine methyl ester, and arginase, with 2( S)-amino- 6-boronohexanoic acid (ABH), significantly reduced O2− production in old rats but not in young. In addition, the ratio of eNOS dimer to monomer in old rats was significantly decreased compared with that shown in young rats. These results suggest that eNOS was uncoupled in old rats. Although the expression of arginase 1 and eNOS was similar in young and old rats, inducible NOS (iNOS) was significantly upregulated. Furthermore, S-nitrosylation of arginase 1 was significantly elevated in old rats. These findings support our previously published finding that iNOS nitrosylates and activates arginase 1 (Santhanam et al., Circ Res 101: 692–702, 2007). Chronic arginase inhibition in old rats preserved eNOS dimer-to-monomer ratio and significantly reduced O2− production and enhanced endothelial-dependent vasorelaxation to ACh. In addition, ABH significantly reduced vascular stiffness in old rats. These data indicate that iNOS-dependent S-nitrosylation of arginase 1 and the increase in arginase activity lead to eNOS uncoupling, contributing to the nitroso-redox imbalance, endothelial dysfunction, and vascular stiffness observed in vascular aging. We suggest that arginase is a viable target for therapy in age-dependent vascular stiffness.

scholarly journals Genderspecific differences of homocysteinemia and its influence on oxidative stress parameters and endothelial function in patients with stable forms of coronary heart disease

2017 ◽  
Vol 95 (8) ◽  
pp. 705-712
Author(s):  
Olga L. Belaya ◽  
K. Yu. Bondar ◽  
L. I. Markova ◽  
Z. V. Kuropteva ◽  
L. M. Baider ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Nitric Oxide ◽  
Coronary Heart Disease ◽  
Heart Disease ◽  
Endothelial Dysfunction ◽  
Endothelial Function ◽  
Gas Liquid Chromatography ◽  
Men And Women ◽  
Stable Forms ◽  
Gender Specific

One of the early manifestations of atherosclerotic lesions is endothelial dysfunction developing under conditions of reduced nitric oxide production, hyperhomocysteinemia, and oxidative stress. Bearing in mind high interest shown to gender-specific peculiarities of cardiovascular diseases, it appears important to study the relationship between these features in men and women with stable forms of coronary heart disease (CHD). Material and methods. The study included 102 patients with sable COPD divided into 2 groups (men and women) and 40 practically healthy subjects. Plasma homocysteine levels were measured by high-resolution gas-liquid chromatography with fluorescent detector with the use of Eko-Novo Milikhrom A-02 apparatus (Russia). Standard methods were used to measure plasma lipids, products of their peroxidation (dienic conjugates and products reacting with 2-thibarbituric acid), antioxidant enzymes (glutathioneperoxidase, and superoxide dismutase in erythrocytes), activity of the ceruloplasmin-transferrin system (by electron paramagnetic resonance method), final metabolites of nitric oxide using the Gries reaction. The endothelial function was studies by ultrasound with the evaluation of endothelium-dependent vasodilation. Results. The mean levels of homocystein and final NO metabolites in men with stable CHD were 1.5 times higher (р=0,01) and 12% lower (р = 0,03) than in women. Endothelial dysfunction was more pronounced in men (р< 0,05). Conclusion. Patients with CHD exhibit significant gender-specific differences in blood levels of of homocystein and final NO metabolites as well as in endothelium-dependent vasoreactivity associated with intensification of lipid peroxidation and impairment of antioxidative protection.

Abstract 3636: The Effects of Arginase II Overexpression on Endothelial Function in Transgenic Mouse Model

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Boris L Vaisman ◽  
Katherine C Wood ◽  
Stephen J Demosky ◽  
Catherine L Knapper ◽  
Jaye Chin-Dusting ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Endothelial Dysfunction ◽  
Transgenic Mice ◽  
Endothelial Function ◽  
Transgenic Mouse ◽  
Plasma Lipid ◽  
Aortic Ring ◽  
Normal Function ◽  
Arginase Activity

Endothelium is a major regulator of local vascular homeostasis. Its normal function is crucial for prevention of the development of atherosclerosis, hypertension and other cardiovascular disorders. Reduced nitric oxide (NO) bioavailability is one of the earliest and most important markers of endothelial dysfunction. L-arginine is the substrate for nitric oxide synthases (NOS). Arginase (Arg) can compete with eNOS for L-arginine and thus may play a role in endothelial dysfunction. To further investigate the role of ArgII in endothelial function and in atherosclerosis we generated transgenic mice with human ArgII (hArgII) gene under control of endothelial-specific Tie2 promoter. Expression of hArgII was measured by RT-PCR in eight tissues of transgenic males and compared with the level of mouse ArgII (mArgII) expression in kidneys of normal C57Bl mice, which was taken as 100%. hArgII was expressed at very high levels in all tissues, especially in aorta (2700%), heart (3500%), kidney (1600%), lung (9860%) and muscle (2000%). Arginase activity was elevated 4.6 – 62 fold in all tissues except liver. Lung endothelial cells isolated from hArgII transgenic mice had 4.4-fold greater of arginase activity than whole lung. Resident peritoneal macrophages from hArgII transgenic and normal mice had similar levels of arginase activity, confirming endothelial specificity of the Tie2 promoter. Overexpression of hArgII neither led to significant changes in plasma level of arginine, citrulline, NOHA, ADMA, SDMA and ornithine, nor to changes in plasma lipid levels. However, ArgII overexpression on apoE-knockout background was accompanied by a 10% increase in plasma total cholesterol (p<0.05). hArgII transgenic mice also had blood pressure (mean arterial and diastolic) that averaged 17% higher than controls. Aortic ring segments from hArgII transgenic mice, precontracted with phenylephrine (10 −6 M), exhibited decreased endothelium-dependent relaxation to increasing concentrations of acetylcholine (10 −9 to 10 −3.5 M), indicating endothelial dysfunction secondary to NO insufficiency. These results show that the Tie2hArgII transgenic mouse is a new model for investigating the role of ArgII in endothelial function and in atherosclerosis.

Regulation of primary hemostasis and vascular endothelial function by glyprolines in metabolic syndrome

2019 ◽  
Author(s):  
М.Е. Григорьева ◽  
Л.А. Ляпина ◽  
Т.Ю. Оберган
Keyword(s):  
Nitric Oxide ◽  
Metabolic Syndrome ◽  
Platelet Aggregation ◽  
Endothelial Dysfunction ◽  
Endothelial Function ◽  
Plasminogen Activator ◽  
Tissue Plasminogen Activator ◽  
Structural Characteristics ◽  
Tissue Plasminogen ◽  
Anticoagulation System

Введение. Метаболический синдром (МС) сопровождается гиперлипемией, гиперкоагуляцией, дисфункцией эндотелия и др. В связи с этим не вызывает сомнений актуальность поиска новых средств комбинированного действия, восстанавливающих как жировой обмен, так и нормальную функцию эндотелия и сосудистотромбоцитарный гемостаз. Цель исследования: изучить в сравнительном аспекте влияние глипролинов ProGlyPro, ProArgPro, ArgProGlyPro и ProGlyProLeu на характеризующие эндотелиальную функцию и состояние сосудистотромбоцитарного гемостаза тканевой активатор плазминогена, уровень конечных метаболитов оксида азота и агрегацию тромбоцитов у крыс с МС. Материалы и методы. Для развития метаболических нарушений крысы получали высококалорийную диету (ВКД). Спустя 6 нед при продолжении ВКД животным интраназально вводили исследуемые пептиды в дозе 50 мкг/кг ежедневно в течение 7 сут. В плазме крови крыс через 20 ч и через 7 сут после последнего введения препаратов определяли показатели системы фибринолиза, АДФагрегацию тромбоцитов, конечные метаболиты оксида азота. Результаты. Развитие МС у крыс приводило к депрессии функции противосвертывающей системы и дисфункции эндотелия. Пролинсодержащие пептиды, применяемые в моделируемых условиях, вызывали активацию антитромбоцитарного звена противосвертывающей системы и эндотелиальной функции. Установлено, что исследуемые глипролины оказывали в кровотоке при их многократном применении выраженные в разной степени однонаправленные изменения в тромбоцитарном гемостазе. Максимальное снижение агрегации тромбоцитов выявлено для ProArgPro. Этот трипептид также в значительной степени активировал сосудистоэндотелиальную функцию путем усиленного выброса в кровоток маркеров тканевого активатора плазминогена и конечных метаболитов оксида азота. Заключение. Наиболее выраженное и устойчивое действие на гемостатическую и эндотелиальную функции в моделируемых условиях у глипролина ProArgPro может быть обусловлено структурными особенностями регуляторных пептидов, а именно, расположением аминокислот аргинина и пролина в непосредственной близости друг от друга. Introduction. Metabolic syndrome (MS) is accompanied by hyperlipemia, hypercoagulability, endothelial dysfunction. The search for new means of combined action, restoring fat metabolism and normal function of the endothelium and platelet hemostasis is relevant. Aim: to study the effect of ProGlyPro, ProArgPro, ArgProGlyPro and ProGlyPro Leu on tissue plasminogen activator, level of final nitric oxide metabolites and platelet aggregation in MS rats. Materials and methods. Rats received a highcalorie diet for the development of MS. After 6 weeks, the peptides were administered intranasally to animals at a dose 50 g/kg daily for 7 days. Parameters of fibrinolysis system, ADPplatelet aggregation, and final metabolites of nitric oxide were determined in rat blood plasma 20 hours and 7 days after the last drugs administration. Results. The development of MS in rats led to depression of anticoagulation system and endothelial dysfunction. Prolinecontaining peptides in simulated conditions caused activation of anticoagulation system and endothelial function. The studied peptides with their repeated use led in the bloodstream to unidirectional changes of varying degrees in platelet haemostasis after their multiple intranasal applications to animals. The maximum reduction in platelet aggregation was detected for ProArgPro. This tripeptide significantly increased the levels of final metabolites of nitric oxide and tissue plasminogen activator. Conclusion. The most pronounced and stable effect on hemostatic and endothelial functions in simulated conditions was identified for ProArgPro. Perhaps this effect is due to the structural characteristics of peptides, namely, the position of arginine in close proximity of proline.

scholarly journals Improvement of endothelial dysfunction in experimental heart failure by chronic RAAS-blockade: ACE-inhibition or AT1-receptor blockade?

2001 ◽  
Vol 2 (1_suppl) ◽  
pp. S64-S69 ◽  
Author(s):  
Lodewijk J Wagenaar ◽  
Hendrik Buikema ◽  
Yigal M Pinto ◽  
Wiek H van Gilst
Keyword(s):  
Oxidative Stress ◽  
Nitric Oxide ◽  
Heart Failure ◽  
Endothelial Dysfunction ◽  
Endothelial Function ◽  
Candesartan Cilexetil ◽  
Ace Inhibition ◽  
At1 Receptor ◽  
Converting Enzyme Inhibitors ◽  
Raas Blockade

Chronic heart failure (CHF) is associated with endothelial dysfunction. Activation of the renin-angiotensin-aldosterone system (RAAS) is believed to be important in the deterioration of endothelial dysfunction in CHF through stimulation of oxidative stress. Whereas angiotensin-converting enzyme inhibitors (ACE-I) improve endothelial function in CHF, the effects of angiotensin II AT1-receptor blockers (ARB) are less well established. Therefore we compared the effects of the ACE-I lisinopril vs. the ARB candesartan on endothelial dysfunction in a rat model of CHF. CHF was induced by myocardial infarction (MI) after coronary ligation. Two weeks after MI, daily treatment with lisinopril (2 mg/kg) or candesartan cilexetil (1.5 mg/kg) was started. After 13 weeks, rats were sacrificed and endothelial function was determined by measuring acetylcholine (ACh)-induced vasodilation in aortic rings, with selective presence of the nitric oxide synthase (NOS)-inhibitor NG-monomethyl-L-arginine (L-NMMA) to determine the contribution of nitric oxide (NO). ACh-induced vasodilation was attenuated in untreated MI (-50%) compared with control rats. This was in part due to an impaired contribution of NO (-49%). Lisinopril and candesartan cilexetil fully normalised ACh-induced dilation, including the part mediated by NO. Chronic RAAS-blockade with lisinopril and candesartan cilexetil normalised endothelial function in CHF in a comparable way. The effect of both treatments included the increase of the NO-mediated dilation, further indicating the important role of oxidative stress in the relationship between the RAAS and endothelial dysfunction in CHF.

Increased expression of iNOS is associated with endothelial dysfunction and impaired pressor responsiveness in streptozotocin-induced diabetes

2005 ◽  
Vol 289 (5) ◽  
pp. H2144-H2152 ◽  
Author(s):  
Prabhakara Reddy Nagareddy ◽  
Zhengyuan Xia ◽  
John H. McNeill ◽  
Kathleen M. MacLeod
Keyword(s):  
Nitric Oxide ◽  
Endothelial Dysfunction ◽  
Nitric Oxide Synthase ◽  
Endothelial Function ◽  
Ang Ii ◽  
Vasoactive Agents ◽  
Duration Of Diabetes ◽  
Cardiovascular Tissues ◽  
Pressor Responses ◽  
Oxide Synthase

Studies in streptozotocin (STZ)-induced diabetic rats have demonstrated cardiovascular abnormalities such as depressed mean arterial blood pressure (MABP) and heart rate (HR), endothelial dysfunction, and attenuated pressor responses to vasoactive agents. We investigated whether these abnormalities are due to diabetes-associated activation of inducible nitric oxide synthase (iNOS). In addition, the effect of the duration of diabetes on these abnormalities was also evaluated. Diabetes was induced by administration of 60 mg/kg STZ via the tail vein. One, 3, 9, or 12 wk after STZ injection, MABP, HR, and endothelial function were measured in conscious unrestrained rats. Pressor response curves to bolus doses of methoxamine (MTX) and angiotensin II (ANG II) were constructed in the presence of N-[3(aminomethyl)benzyl]-acetamidine, dihydrochloride (1400W), a specific inhibitor of iNOS. Depressed MABP and HR and impairment of endothelial function were observed as early as 3 wk after induction of diabetes. Acute inhibition of iNOS with 1400W (3 mg/kg iv) restored the attenuated pressor responses to both MTX and ANG II without affecting the basal MABP and HR. Immunohistochemical and Western analysis blot studies in cardiovascular tissues revealed decreased expression of endothelial nitric oxide synthase (eNOS) concomitant with increased expression of iNOS and nitrotyrosine with the progression of diabetes. Our findings suggest that induction of iNOS in cardiovascular tissues is dependent on the duration of diabetes and contributes significantly to the depressed pressor responses to vasoactive agents and potentially to endothelial dysfunction.

scholarly journals Expression of Endomyocardial Nitric Oxide Synthase and Coronary Endothelial Function in Human Cardiac Allografts

Circulation ◽  
2001 ◽  
Vol 104 (suppl_1) ◽  
Author(s):  
Stephen M. Wildhirt ◽  
Michael Weis ◽  
Costas Schulze ◽  
Nicole Conrad ◽  
Sinan Pehlivanli ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Endothelial Dysfunction ◽  
Nitric Oxide Synthase ◽  
Endothelial Function ◽  
Heart Transplantation ◽  
Mrna Expression ◽  
Inos Mrna ◽  
Inos Protein ◽  
Cardiac Allografts ◽  
Oxide Synthase

Background Inducible nitric oxide synthase (iNOS) is expressed and is functionally active in the presence of transplant arteriosclerosis. However, the early involvement of iNOS in alterations of microvascular endothelial function in the absence of preexisting lesions remains unclear; this information would be of prognostic value. We studied the course of iNOS mRNA expression, transcardiac nitric oxide production, and their potential association with microvascular coronary endothelial dysfunction in human cardiac allografts. Methods and Results A total of 42 patients were studied at 1, 6, and 12 months after heart transplantation. Microvascular coronary flow velocity reserve (CFVR) was tested in an endothelium-dependent (acetylcholine) and -independent manner (adenosine) using a Doppler flow wire. Endomyocardial iNOS expression was determined by reverse transcription polymerase chain reaction. iNOS protein and nitrotyrosine levels were detected by immunohistochemistry. Transcardiac plasma nitrite/nitrate (NOx) levels were measured by the Griess reaction. CFVR was impaired in 26.1% of patients (n=11) at 1 month and in 31% of patients (n=13) at 12 months after heart transplantation. Patients who developed impaired CFVR in the first year showed a significant increase in iNOS gene expression. Patients with impairment of CFVR 1 month after heart transplantation had higher levels of iNOS mRNA than patients with a normal CFVR. Patients with an initial impairment of CFVR who did not improve over time presented with significantly higher iNOS mRNA levels. iNOS protein and nitrotyrosine were expressed in the endomyocardial vessels of patients with impaired CFVR. Transcardiac NOx release was higher in patients with impaired CFVR. Conclusions In human cardiac allografts, microvascular endothelial dysfunction is associated with an enhanced endomyocardial iNOS mRNA expression and higher transcardiac NOx production and is accompanied by the expression of nitrotyrosine protein, suggesting peroxynitrite plays a role in the disease process. The data from the present study suggest an important role for the iNOS/nitric oxide pathway in the regulation of microvascular function in the absence of preexisting atherosclerotic lesions.

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.

scholarly journals Amyloidogenic medin induces endothelial dysfunction and vascular inflammation through the receptor for advanced glycation endproducts

2017 ◽  
Vol 113 (11) ◽  
pp. 1389-1402 ◽  
Author(s):  
Raymond Q. Migrino ◽  
Hannah A. Davies ◽  
Seth Truran ◽  
Nina Karamanova ◽  
Daniel A. Franco ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Endothelial Cells ◽  
Endothelial Cell ◽  
Endothelial Dysfunction ◽  
Endothelial Function ◽  
Advanced Glycation Endproducts ◽  
Advanced Glycation ◽  
Inflammatory Signaling ◽  
Glycation Endproducts ◽  
Nitrative Stress

AbstractAimsMedin is a common amyloidogenic protein in humans that accumulates in arteries with advanced age and has been implicated in vascular degeneration. Medin’s effect on endothelial function remains unknown. The aims are to assess medin’s effects on human arteriole endothelial function and identify potential mechanisms underlying medin-induced vascular injury.Methods and resultsEx vivo human adipose and leptomeningeal arterioles were exposed (1 h) to medin (0.1, 1, or 5 µM) without or with FPS–ZM1 [100 µM, receptor for advanced glycation endproducts (RAGE)-specific inhibitor] and endothelium-dependent function (acetylcholine dilator response) and endothelium-independent function (dilator response to nitric oxide donor diethylenetriamine NONOate) were compared with baseline control. Human umbilical vein endothelial cells were exposed to medin without or with FPS–ZM1 and oxidative and nitrative stress, cell viability, and pro-inflammatory signaling measures were obtained. Medin caused impaired endothelial function (vs. baseline response: −45.2 ± 5.1 and −35.8 ± 7.9% in adipose and leptomeningeal arterioles, respectively, each P < 0.05). Dilator response to NONOate was not significantly changed. Medin decreased arteriole and endothelial cell nitric oxide production, increased superoxide production, reduced endothelial cell viability, proliferation, and migration. Medin increased gene and protein expression of interleukin-6 and interleukin-8 via activation of nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB). Medin-induced endothelial dysfunction and oxidative stress were reversed by antioxidant polyethylene glycol superoxide dismutase and by RAGE inhibitor FPS-ZM1.ConclusionsMedin causes human microvascular endothelial dysfunction through oxidative and nitrative stress and promotes pro-inflammatory signaling in endothelial cells. These effects appear to be mediated via RAGE. The findings represent a potential novel mechanism of vascular injury.

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