Endothelial Dysfunction In Hypertension Research Articles

Role of thioredoxin-interacting protein in mediating endothelial dysfunction in hypertension

Excessive oxidative stress is a major causative factor of endothelial dysfunction in hypertension. As an endogenous pro-oxidant, thioredoxin-interacting protein (TXNIP) contributes to oxidative damage in various tissues. The present study aimed to investigate the role of TXNIP in mediating endothelial dysfunction in hypertension. In vivo, an experimental model of acquired hypertension was established with two-kidney, one-clip (2K1C) surgery. The expression of TXNIP in the vascular endothelial cells of multiple vessels was significantly increased in hypertensive rats compared with sham-operated rats. Resveratrol, a TXNIP inhibitor, suppressed vascular oxidative damage and increased the expression and activity of eNOS in the aorta of hypertensive rats. Notably, impaired endothelium-dependent vasodilation was effectively improved by TXNIP inhibition in hypertensive rats. In vitro, we observed that Ang II increased the expression of TXNIP in primary human aortic endothelial cells (HAECs) and that TXNIP knockdown by RNA interference alleviated cellular oxidative stress damage and mitigated the impaired eNOS activation and intracellular nitric oxide (NO) production observed in Ang II-treated HAECs. However, inhibiting thioredoxin (TRX) with PX-12 completely blunted the protective effect of silencing TXNIP. In addition, TXNIP knockdown facilitated TRX expression and promoted TRX nuclear translocation to further activate AP1 and REF1. TRX overexpression exhibited favorable effects on eNOS/NO homeostasis in Ang II-treated HAECs. Thus, TXNIP contributes to oxidative stress and endothelial dysfunction in hypertension, and these effects are dependent on the antioxidant capacity of TRX, suggesting that targeting TXNIP may be a novel strategy for antihypertensive therapy.

A greater burden of atrial fibrillation is associated with worse endothelial dysfunction in hypertension.

Atrial fibrillation (AF) and hypertension often co-exist and both are associated with endothelial dysfunction. We hypothesised that AF would further worsen endothelium-dependent flow-mediated dilatation (FMD) in hypertension patients compared to those without AF. In a cross-sectional comparison, we measured brachial artery diameter at rest and during reactive hyperaemia following 5 min of arterial occlusion in two patient groups: AF (and hypertension) (n = 61) and hypertension control groups (n = 33). The AF (and hypertension) subgroups: permanent AF (n = 30) and paroxysmal AF (n = 31) were also assessed. The permanent AF patients received heart rate and blood pressure (BP) control optimisation and were then followed up after eight weeks for repeat FMD testing. There was no significant difference in FMD between AF (and hypertension) group and hypertension control group (4.6%, 95% CI [2.6-5.9%] vs 2.6%, 95% CI [1.9-5.3%]; p = 0.25). There was a significant difference in FMD between permanent AF and paroxysmal AF groups (3.1%, 95% CI [2.3-4.8%] vs 5.9%, 95% CI [4.0-8.1%]; p = 0.02). Endothelium-dependent FMD response showed a non-significant improvement trend following eight weeks of heart rate and BP optimisation (3.1%, 95% CI [2.3-4.8%] (baseline) vs 5.2%, 95% CI [3.9-6.5%] (follow up), p = 0.09). Presence of AF generally does not incrementally worsen endothelial dysfunction in hypertension patients, although the duration and frequency of AF (paroxysmal AF to permanent AF) does lead to worsening endothelial function. Eight weeks of BP optimisation did not significantly improve endothelial dysfunction as measured by FMD.

Serum γ-Glutamyltransferase Concentration Predicts Endothelial Dysfunction in Naïve Hypertensive Patients

Background: Serum gamma-glutamyltransferase (γ-GT) is recognized as a risk factor for cardiovascular diseases (CV). Traditional cardiovascular risk factors mediate endothelial dysfunction. Aim: to evaluate a possible correlation between serum γ-GT and endothelium-dependent vasodilation in naïve hypertensives. Methods: We enrolled 500 hypertensives. Endothelial function was studied by strain-gauge plethysmography. Receiver operating characteristic (ROC) analysis was used to assess the predictive value of γ-GT and to identify the optimal cut-off value of the same variable for endothelial dysfunction. Results: At univariate linear analysis peak percent increase in acetylcholine (ACh)-stimulated vasodilation was inversely related to γ-GT (r = −0.587), alanine aminotransferase (ALT) (r = −0.559), aspartate aminotransferase (AST) (r = −0.464), age (r = −0.171), body mass index (BMI) (r = −0.152), and fasting glucose (r = −101). In the stepwise multivariate regression model, endothelium-dependent vasodilation was significantly related to γ-GT (β = −0.362), ALT (β = −0.297), AST (β = −0.217), estimated glomerular filtration rate (e-GFR) (β = 0.199), gender (β = 0.166), and smoking (β = −0.061). The ROC analysis demonstrated that the accuracy of γ-GT for identifying patients with endothelial dysfunction was 82.1%; the optimal γ-GT cut-off value for discriminating patients with this alteration was 27 UI/L. Conclusions: Serum γ-GT values, within the normal range, are significantly associated with endothelial dysfunction in hypertensives, and may be considered a biomarker of early vascular damage.

A Study on Assessment of Endothelial Dysfunction in Hypertension

A Study on Assessment of Endothelial Dysfunction in Hypertension

Endothelial dysfunction in hypertension: cause or effect?

Hypertension remains a pandemic of the 21st century, being a major factor of premature death. The introduction of imaging methods into clinical practice revealed a high prevalence of target organ damage mediated by hypertension. One of the systemic target organs in hypertension is endothelium. Its damage plays an important role in the initiation of the cardiovascular disease continuum. On the other hand, structure and function defects of the endothelium is considered as a possible reason for the increase in blood pressure. This literature review systematizes data on a causal relationship between hypertension and endothelial dysfunction, and discusses the direction of further study of vascular endothelium function.

Association of oxidative stress and endothelial dysfunction in hypertension

BackgroundBiomarkers of oxidative stress (OS) are involved in the pathophysiology of hypertension (HTN) and endothelial dysfunction is also related to HTN. Still, a significant association of OS, as well as endothelial function, remains unclear in HTN. MethodsTotalling 222 North Indian peoples aged 18–80 participated in the study. Of these participants, 74 were elderly hypertensive subjects (age ≥60 years), and 128 were normotensive subjects (age ≥60 years-control I; n = 74, and <60 years-control II; n = 74). OS was assessed by measurement of total oxidant status (TOS) and total antioxidant status (TAS) using a colorimetric and automated method developed by Erel O. Endothelial dysfunction was assessed by measurement of flow-mediated dilation (FMD) using doppler ultrasound system. ResultsTOS and OSI were significantly increased and TAS and FMD significantly decreased in patients with HTN as compared to control I and control II. The increase in the level of TOS and a decrease in the level of TAS and FMD were also evident with advancing age. FMD was negatively correlated with TOS and positively correlated with TAS. ConclusionDecreased TAS level, increased TOS level reflect OS that may be the reason for reduced FMD in elderly hypertensive patients.

Endothelial dysfunction, subclinical atherosclerosis and LDL cholesterol are the independent predictors of left atrial functions in hypertension.

Left atrial function has an important role in determining optimal performance of the heart. Increase of left atrial dysfunction and volume are poor prognostic factors. In this study, we investigated independent determinants of left atrial function in non-diabetic patients with de novo hypertension. The study included 124 consecutive non-diabetic patients with de novo hypertension. Brachial artery flow-mediated dilatation, carotid intima-media thickness, transthoracic echocardiography, 24-h rhythm holter, and aortic stiffness measurements were recorded. In echocardiography, left atrial maximum (LAMaV) and minimum (LAMiV) volumes were calculated. Left atrium total emptying fraction (LATEF) and total emptying volume (LATEV) were divided into two groups according to the mean levels. Multivariate analysis was performed after correlation analysis for LATEV and LATEF mean levels. By logistic regression analysis, systolic blood pressure (OR 0.882, 95% CI 0.784-0.992, p = 0.036), percent of flow-mediated dilation (OR 0.747, 95% CI 0.595-0.938, p = 0.012), and presence of carotid plaque (OR 0.014, 95% CI 0.001-0.188, p = 0.001) were found as independent variables that determine LATEF. Age (OR 0.879, 95% CI 0.795-0.972, p = 0.012), smoking (OR 23.739, 95% CI 2.699-208.810, p = 0.004), left ventricular mass index (OR 1.052, 95% CI 1.012-1.094, p = 0.011), mitrale E-wave velocity (OR 1.108, 95% CI 1.031-1.191, p = 0.005) and LDL (low-density lipoprotein) cholesterol (OR 0.942, 95% CI 0.911-0.974, p = 0.001) were independent predictors of LATEV. In non-diabetic patients with de novo hypertension endothelial dysfunction, subclinical atherosclerosis and LDL cholesterol levels independently affect left atrial function.

Relationship between circulating microparticles and hypertension and other cardiac disease biomarkers in the elderly

BackgroundMicroparticles are procoagulant membrane vesicles that play role in endothelium dysfunction pathogenesis and are increased in hypertension, acute/chronic vascular pathological events. Here; we aimed to compare MPs levels of hypertensive geriatric patients with healthy age-match-patients, discuss its availability as a cardiovascular biomarker and investigate its relationship with other inflammatory markers.MethodsForty seven hypertensive geriatric patients (M/F;15/32) and 47 healthy controls (M/F;19/28) were included in the study. MPs levels were examined functionally through thrombin generation test (TGT) parameters (MPS Lag time, MPS ETP, MPs Peak, MPS start Tail) and compared with CRP, N/L ratio, ALT, GGT, thrombocyte parameters. Decrease in MPS Lag time, increase in MPS ETS and MPs Peak elevation were accepted as tendency to coagulation which meant an increase in number and function of MPs.ResultsNo significant difference was found between 2 groups for MPS tests (MPS Lag time, MPS ETP, MPs Peak, MPS start Tail). Platelet count was significantly higher in hypertensive patient group. There was a negative correlation between age and MPs Peak, MPS Lag time. There was a positive correlation between CRP and MPS ETP, MPs Peak values.ConclusionsOur present findings might help to understand the hemostasis via TGT parameters, in the elderly. Contribution of MPs to thrombosis tendency seen with aging and increased number of circulating MPs caused by hypertensive endothelial dysfunction must be taken into consideration. MPs might be accepted as vascular inflammation and damage markers and used as follow up tools of medical treatment of vascular inflammation-related diseases.

Monoamine Oxidase-Related Vascular Oxidative Stress in Diseases Associated with Inflammatory Burden.

Monoamine oxidases (MAO) with 2 isoforms, A and B, located at the outer mitochondrial membrane are flavoenzyme membranes with a major role in the metabolism of monoaminergic neurotransmitters and biogenic amines in the central nervous system and peripheral tissues, respectively. In the process of oxidative deamination, aldehydes, hydrogen peroxide, and ammonia are constantly generated as potential deleterious by-products. While being systematically studied for decades as sources of reactive oxygen species in brain diseases, compelling evidence nowadays supports the role of MAO-related oxidative stress in cardiovascular and metabolic pathologies. Indeed, oxidative stress and chronic inflammation are the most common pathomechanisms of the main noncommunicable diseases of our century. MAO inhibition with the new generation of reversible and selective drugs has recently emerged as a pharmacological strategy aimed at mitigating both processes. The aim of this minireview is to summarize available information regarding the contribution of MAO to the vascular oxidative stress and endothelial dysfunction in hypertension, metabolic disorders, and chronic kidney disease, all conditions associated with increased inflammatory burden.

Abstract P193: The Use of Antihypertensive Drugs, But Not Optimal Blood Pressure Level Was a Predictor of Endothelial Dysfunction in Hypertensives: From Multicenter Prospective Observational Study: FMD-J Study

Background: The predictors of endothelial dysfunction, the initial marker of the development of atherosclerosis, have not been fully clarified. One previous observational study suggested that antihypertensive treatment in hypertensives may be associated with better endothelial function. However, it is not known whether antihypertensive treatment is associated with endothelial function independent from blood pressure level. The objective of this study is to evaluate the association of the use of antihypertensive drugs and blood pressure with endothelial function in the multicenter prospective observational study, FMD-J study. Methods: 685 hypertensive subjects (mean age 62 ± 9 years) in the FMD-J study were followed for 3 years. Endothelial function was evaluated by flow mediated dilation (FMD). The FMD and the conventional risk factors for cardiovascular disease (CVD) were measured at the baseline and the end of the 3-year study period. We defined endothelial dysfunction as continuation of FMD &amp;gt 4% for 3 years. Also, normal endothelial function was defined as continuation of FMD &amp;gt 7 % for 3 years. Multivariate logistic regression analysis adjusted for established CVD risk factors were performed to assess the associations of antihypertensive treatment and endothelial dysfunction / normal endothelial function. We also evaluated whether the class of antihypertensive drugs was associated with endothelial function. Results: 155 subjects had endothelial dysfunction and 71 subjects had normal endothelial function. The multivariate logistic regression analysis revealed that the use of antihypertensive drugs was associated with lower risk of endothelial dysfunction with odds ratio (OR) (95% CI) of 0.20 (0.50-0.86, P=0.03), independent of blood pressure. The use of antihypertensive drugs was also significantly associated with increase of normal endothelial function with OR of .6.28 (2.86-13.80, P &amp;gt 0.001). In contrast, controlling of systolic blood pressure to optimal blood pressure level (&amp;g t130 mm Hg) was associated with neither endothelial dysfunction nor endothelial function. This association was not altered, even when subjects’ systolic blood pressure was controlled to &amp;gt 120 mm Hg. Among the class of antihypertensive drugs, only calcium-channel-blockers, ACE-inhibitors, and ARBs were associated with endothelial function, but diuretics and beta-blockers were not associated with endothelial function. Conclusion: The use of antihypertensive medication, but not optimal blood pressure control was associated with lower risk of endothelial dysfunction in hypertensives. This association seemed to be only limited in calcium-channel-blockers, ACE-inhibitors, and ARBs. Further investigation why the use of antihypertensive drugs was associated with endothelial function independent of blood pressure level, may provide valuable insights into prevention of CVD.

Tobacco smoking induces cardiovascular mitochondrial oxidative stress, promotes endothelial dysfunction, and enhances hypertension

Tobacco smoking is a major risk factor for cardiovascular disease and hypertension. It is associated with the oxidative stress and induces metabolic reprogramming, altering mitochondrial function. We hypothesized that cigarette smoke induces cardiovascular mitochondrial oxidative stress, which contributes to endothelial dysfunction and hypertension. To test this hypothesis, we studied whether the scavenging of mitochondrial H2O2 in transgenic mice expressing mitochondria-targeted catalase (mCAT) attenuates the development of cigarette smoke/angiotensin II-induced mitochondrial oxidative stress and hypertension compared with wild-type mice. Two weeks of exposure of wild-type mice with cigarette smoke increased systolic blood pressure by 17 mmHg, which was similar to the effect of a subpresssor dose of angiotensin II (0.2 mg·kg-1·day-1), leading to a moderate increase to the prehypertensive level. Cigarette smoke exposure and a low dose of angiotensin II cooperatively induced severe hypertension in wild-type mice, but the scavenging of mitochondrial H2O2 in mCAT mice completely prevented the development of hypertension. Cigarette smoke and angiotensin II cooperatively induced oxidation of cardiolipin (a specific biomarker of mitochondrial oxidative stress) in wild-type mice, which was abolished in mCAT mice. Cigarette smoke and angiotensin II impaired endothelium-dependent relaxation and induced superoxide overproduction, which was diminished in mCAT mice. To mimic the tobacco smoke exposure, we used cigarette smoke condensate, which induced mitochondrial superoxide overproduction and reduced endothelial nitric oxide (a hallmark of endothelial dysfunction in hypertension). Western blot experiments indicated that tobacco smoke and angiotensin II reduce the mitochondrial deacetylase sirtuin-3 level and cause hyperacetylation of a key mitochondrial antioxidant, SOD2, which promotes mitochondrial oxidative stress. NEW & NOTEWORTHY This work demonstrates tobacco smoking-induced mitochondrial oxidative stress, which contributes to endothelial dysfunction and development of hypertension. We suggest that the targeting of mitochondrial oxidative stress can be beneficial for treatment of pathological conditions associated with tobacco smoking, such as endothelial dysfunction, hypertension, and cardiovascular diseases.

Abstract 025: Cellular Mechanisms of Blood-Brain Barrier Disruption in Ang II-Induced Hypertension

The blood-brain barrier (BBB) is critically important for brain health by regulating molecular exchanges between blood and brain. Hypertension (HTN) induces breakdown of the BBB which may contribute to its deleterious effect on the brain, but the cellular bases of the BBB opening remain to be established. We used a model of angiotensin II (AngII) HTN (600ng/kg/min x 2 weeks; n&gt;5/group) to investigate the mechanisms of the BBB opening. BBB permeability was assessed spectrophotometrically in C57BL/6J mice using 3000 MW FITC-dextran as a tracer. HTN increased BBB permeability in Ang II HTN (29.8 ± 0.9 vs 18.1 ± 0.5 ng/g in control, p&lt;0.01), an effect partially ameliorated by the angiotensin type 1 receptor (AT1R) antagonist losartan in the drinking water (22.9 ± 0.6 ng/g) but not by hydralazine + hydrochlorothiazide (27.4 ± 0.7 ng/g), suggesting involvement of AT1R and not elevated blood pressure. Next, we sought to identify the mechanisms of the breakdown of the BBB in HTN. First, we used electron microscopy to examine the ultrastructure of endothelial tight junctions (TJ) and assess vesicular transport, key components of the BBB. HTN reduced the length (-25%) and complexity (-11%) of TJ, and increased the number of endothelial vesicles (2.22 vs 1.42 vesicles/endothelial area, p&lt;0.05). The TJ remodeling was associated with a reduction in occludin (-17%, p&lt;0.01) and claudin-5 (-30%, p&lt;0.05) mRNA in microvascular preparations. Additionally, the expression of Mfsd2a, a lipid transporter that also suppresses vesicular transcytosis, was markedly attenuated (-43%, p&lt;0.01). Taken together, these data suggest a strong effect of Ang II on cerebral endothelial cells to induce BBB opening. Since perivascular macrophages (PVM) mediate cerebral endothelial dysfunction in HTN (J Clin Invest 2016;126:4674), we tested their involvement in the BBB opening. PVM depletion with icv clodronate or deletion of AT1 receptors in PVM partially attenuated the BBB opening in Ang II HTN (p&lt;0.05). Thus, we conclude that AT1R in cerebral endothelial cells and PVM mediate the BBB opening by targeting both paracellular and vesicular transport. Such increase in BBB permeability to circulating agents may contribute to the cerebrovascular and cognitive dysfunction associated with HTN.

MPGES-1 (Microsomal Prostaglandin E Synthase-1) Mediates Vascular Dysfunction in Hypertension Through Oxidative Stress.

mPGES-1 (microsomal prostaglandin E synthase-1), the downstream enzyme responsible for PGE2 (prostaglandin E2) synthesis in inflammatory conditions and oxidative stress are increased in vessels from hypertensive animals. We evaluated the role of mPGES-1-derived PGE2 in the vascular dysfunction and remodeling in hypertension and the possible contribution of oxidative stress. We used human peripheral blood mononuclear cells from asymptomatic patients, arteries from untreated and Ang II (angiotensin II)-infused mPGES-1-/- and mPGES-1+/+ mice, and vascular smooth muscle cells exposed to PGE2 In human cells, we found a positive correlation between mPGES-1 mRNA and carotid intima-media thickness (r=0.637; P<0.001) and with NADPH oxidase-dependent superoxide production (r=0.417; P<0.001). In Ang II-infused mice, mPGES-1 deletion prevented all of the following: (1) the augmented wall:lumen ratio, vascular stiffness, and altered elastin structure; (2) the increased gene expression of profibrotic and proinflammatory markers; (3) the increased vasoconstrictor responses and endothelial dysfunction; (4) the increased NADPH oxidase activity and the diminished mitochondrial membrane potential; and (5) the increased reactive oxygen species generation and reduced NO bioavailability. In vascular smooth muscle cells or aortic segments, PGE2 increased NADPH oxidase expression and activity and reduced mitochondrial membrane potential, effects that were abolished by antagonists of the PGE2 receptors (EP), EP1 and EP3, and by JNK (c-Jun N-terminal kinase) and ERK1/2 (extracellular-signal-regulated kinases 1/2) inhibition. Deletion of mPGES-1 augmented vascular production of PGI2 suggesting rediversion of the accumulated PGH2 substrate. In conclusion, mPGES-1-derived PGE2 is involved in vascular remodeling, stiffness, and endothelial dysfunction in hypertension likely through an increase of oxidative stress produced by NADPH oxidase and mitochondria.

Hydrogen sulfide improves endothelial dysfunction through inhibition of the vicious circle of NLRP3 and oxidative stress in spontaneously hypertensive rats

AimsThe aim of this study is to elucidate whether the inhibition of inflammasome and oxidative stress mediated the ameliorative effect of hydrogen sulfide (H2S) on endothelial dysfunction in hypertension.MethodsSpontaneously hypertensive rats (SHR) and normotensive Wistar kyoto rats (WKY) were injected with 100 μM NaSH intraperitoneally daily for 16 weeks. Systolic blood pressure (SBP) and plasma MDA and IL‐1β were measured. Renal vascular was used to determine endothelial dependent contraction (EDC) and endothelial dependent relaxation (EDR). Protein levels were detected by Western blot. Human umbilical vein endothelial cells (HUVECs) were used to confirm the protective role of H2S against AngII‐induced cell injury.ResultsExogenous NaSH administration significantly lowered SBP and ameliorated damaged EDR and EDC. H2S reduced the activation of NLRP3 inflammasome and oxidative stress in SHR. The endothelial protective and anti‐oxidant effect of H2S was abolished by LPS, an inducer of NLRP3 inflammasome. In HUVECs, H2S significantly ameliorated AngII‐induced cellular impairment, NLRP3 inflammasome and ROS generation. After knocking down of Nrf2, the above protective effect of H2S was abolished.ConclusionHydrogen sulfide could inhibit vicious circle of oxidative stress and inflammation, resulted in improved endothelial function and ameliorated hypertension. Our results throw light on the crucial role of H2S in regulation of endothelial function, which might provide the new target for treatment of hypertension.Support or Funding InformationThis work was supported by the National Natural Science Foundation of China (31171098, 31671185), the Specialized Research Fund for the Doctoral Program of Higher Education of China (20121323110008), the Hebei Province for Innovation Talents Support Plan (LJRC017) and the Natural Science Foundation of Hebei (C2012206063, H2016206264).This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Targeting Mitochondrial Deacetylase Sirt3 in Endothelial Dysfunction and Hypertension

Hypertension is a multifactorial disorder involving perturbations of the vasculature, the kidney and the central nervous system. It represents a major risk factor for stroke, myocardial infarction, and heart failure; however, despite treatment with multiple drugs, one third of hypertensive patients remain hypertensive. We have recently shown that hypertension is associated with mitochondrial hyperacetylation due to reduced activity of the key mitochondrial deacetylase Sirt3 (Dikalova et al. Circ Res. 2017;121(5):564–574.). We hypothesized that targeting Sirt3 has therapeutic potential in endothelial dysfunction and hypertension. To test this hypothesis we have developed novel tamoxifen-inducible endothelium specific Sirt3 knockout (EcSirt3KO), inducible endothelial specific Sirt3 overexpressing (EcSirt3OX) mice and global Sirt3 overexpressing (Sirt3OX) on C57Bl/6J background, and examined the effect of Sirt3 expression on vascular dysfunction and hypertension. Blood pressure was measured by telemetry. Vascular superoxide was measured by HPLC analysis of O2• specific products of DHE and mitoSOX. Vascular NO was measured by EPR and NO spin trap Fe(DETC)2. Vascular reactivity was studied using isometric tension and vascular permeability was tested by Evans Blue assay. Angiotensin II-induced hypertension was markedly increased in EcSirt3KO compared with wild-type C57Bl/6J mice. Decrease of NO is a hallmark of endothelial dysfunction in hypertension due to vascular oxidative stress. Indeed, angiotensin II infusion in EcSirt3KO mice causes severe loss of endothelial nitric oxide (3-fold vs 2-fold in wild-type), overproduction of vascular superoxide, exacerbated endothelial dysfunction and increased vascular permeability. In contrast to EcSirt3KO, Sirt3 overexpression in Sirt3OX mice significantly attenuates hypertension by 25 mm Hg, prevents overproduction of vascular superoxide, protects endothelial dependent relaxation and vascular permeability. Interestingly, endothelial specific Sirt3 overexpression in EcSirt3OX mice mimics the protective effect of global Sirt3 overexpression by blocking vascular oxidative stress, protecting vascular relaxation and attenuating angiotensin II-induced hypertension. Our studies demonstrate that endothelial Sirt3 protects vascular functions and attenuates hypertension. These data support a therapeutic potential of targeting Sirt3 in vascular dysfunction and hypertension. Support or Funding Information This work was supported by funding from National Institute of Health (R01HL124116 and PO1HL129941), Vanderbilt University (VR7040 and UL1 RR024975). Dr. Dikalova was supported by American Heart Association (16GRNT31230017) and Dr. Itani was funded by the National Institute of Health (1F32HL124972). Vascular relaxation in wild-type and Sirt3OX mice before and after angiotensin II-infusion (0.7 mg/kg/day). Vascular reactivity was studied using isometric tension (B). Blood pressure in wild-type and Sirt3OX mice. (A) Systolic blood pressure was measured by telemetry before and after angiotensin II-infusion (0.7 mg/kg/day). Insert shows Western blot of Sirt3 and SOD2 in aorta mitochondria isolated from WT and Sirt3OX mice. Aaortic superoxide in wild-type and Sirt3OX mice before and after angiotensin II-infusion (0.7 mg/kg/day) was measured by DHE/HPLC assay (C). Results are mean ± SEM (n=5). *P<0.01 vs WT. **P<0.05 vs WT+AngII. Aortic endothelial nitric oxide in wild-type and Sirt3OX mice before and after angiotensin II-infusion (0.7 mg/kg/day) was measured by Electron Spin Resonance (D). Results are mean ± SEM (n=5). *P<0.01 vs WT. **P<0.05 vs WT+AngII. This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Hydrogen sulfide improves endothelial dysfunction in hypertension by activating peroxisome proliferator-activated receptor delta/endothelial nitric oxide synthase signaling.

We aimed to elucidate the ameliorative effect of hydrogen sulfide (H2S) on endothelium-dependent relaxation disturbances via peroxisome proliferator-activated receptor delta/endothelial nitric oxide synthase (PPARδ/eNOS) pathway activation in hypertensive patients and rats. Renal arteries were collected from normotensive and hypertensive patients who underwent nephron-sparing surgery. Renal arteries from 37 patients were cultured with or without sodium H2S (NaHS) 50 μmol/l. The rats were randomly divided into four groups: Sham; Sham + NaHS, two kidneys; one clipped (2K1C); and 2K1C + NaHS. Mean arterial pressure was measured by tail-cuff plethysmography. A microvessel recording technique was used to observe the effect of NaHS on endothelium-dependent relaxation. Plasma H2S concentrations were detected using the monobromobimane method. Real-time PCR and western blotting were used to assess mRNA and protein levels of AT1, cystathionine γ-lyase, PPARδ, and phosphor-eNOS. Laser confocal scanning microscopy measured intracellular NO production in human umbilical vein endothelial cells. NaHS improved endothelial function in hypertensive humans and rats. The 20-week administration of NaHS to 2K1C rats lowered the mean arterial pressure. In human umbilical vein endothelial cells, NaHS improved the AngII-induced production of NO. NaHS upregulated PPARδ expression, increased protein kinase B (Akt) or adenosine monophosphate kinase-activated protein kinase (AMPK) phosphorylation, and enhanced eNOS phosphorylation. A PPARδ agonist could mimic the ameliorative effect of NaHS that was suppressed by PPARδ, AMPK, or Akt inhibition. H2S plays a protective function in renal arterial endothelium in hypertension by activating the PPARδ/PI3K/Akt/eNOS or PPARδ/AMPK/eNOS pathway. H2S may serve as an effective strategy against hypertension.

Tetramethylpyrazine suppresses angiotensin II-induced soluble epoxide hydrolase expression in coronary endothelium via anti-ER stress mechanism

Activation of soluble epoxide hydrolase (sEH) is associated with endothelial dysfunction in hypertension, though the underlying mechanisms are inadequately understood and the role of endoplasmic reticulum (ER) stress is yet to be studied in detail. Tetramethylpyrazine (TMP), a major bioactive ingredient of Chinese herb Chuanxiong, is well-known for its cardiovascular benefits. Nevertheless, whether TMP may protect vascular endothelium from ER stress and whether regulation of sEH is involved remain unknown. This study aimed at investigating the role of ER stress in angiotensin-II (Ang-II)-induced sEH dysregulation and elucidating the significance of ER stress regulation in the vasoprotective effect of TMP. Porcine primary coronary artery endothelial cells (PCECs) were used for western blot, ELISA, and reverse-transcription PCR analysis. Porcine coronary arteries were assessed in a myograph for endothelial dilator function. Ang-II induced expression of ER stress molecules in PCECs meanwhile enhanced sEH expression and decreased 11,12-EET. Exposure of PCECs to the chemical ER stress inducer tunicamycin also increased sEH expression. Inhibition of ER stress suppressed sEH upregulation, resulting in an increase of 11,12-EET. The impairment of endothelium-dependent vasorelaxation induced by Ang-II or tunicamycin was ameliorated by inhibitors of ER stress or sEH. TMP showed comparable inhibitory effect to ER stress inhibitors on the expression of ER stress molecules, the dysregulation of sEH/EET, and the impairment of endothelial dilator function. We demonstrated that ER stress mediates Ang-II-induced sEH upregulation in coronary endothelium. TMP has potent anti-ER stress capacity through which TMP normalizes sEH expression and confers protective effect against Ang-II on endothelial function of coronary arteries.

Exercise and Endothelial Dysfunction in Hypertension

Vascular endothelium normally maintains cardiovascular homeostasis by secreting the vasoactive substances. Many evidences indicate that endothelial dysfunction plays a pivotal role in the initiation, development, and progression of several cardiovascular diseases (CVDs). Hypertension, one among the CVDs, is associated with morphological and functional alterations of vascular system, especially endothelial dysfunction. The complicated mechanisms underlying endothelial dysfunction involve the inflammation, increased oxidative stress, and impaired nitric oxide (NO) production and vasorelaxation. It has been evident that aerobic exercise training evokes the improvements in anti-inflammation, antioxidant production, NO bioavailability, and endothelium-dependent vasorelaxation. This partly explains the blood pressure-lowering and beneficial vascular effects of exercise in hypertension. Further research could be focused on the integration of aerobic and resistance exercise for the improvements in cardiovascular function as an antihypertensive tool. Our review may provide the current understanding of beneficial effects and physiological mechanisms of exercise intervention for prevention and treatment of hypertension.

Role of MicroRNA in Endothelial Dysfunction and Hypertension.

Purpose of ReviewHypertension is either a cause or a consequence of the endothelial dysfunction and a major risk factor for cardiovascular disease (CVD). In vitro and in vivo studies established that microRNAs (miRNAs) are decisive for endothelial cell gene expression and function in various pathological conditions associated with CVD.This review provides an overview of the miRNA role in controlling the key connections between endothelial dysfunction and hypertension.Recent FindingsHerein we summarize the present understanding of mechanisms underlying hypertension and its associated endothelial dysfunction as well as the miRNA role in endothelial cells with accent on the modulation of renin-angiotensin-aldosterone-system, nitric oxide, oxidative stress and on the control of vascular inflammation and angiogenesis in relation to endothelial dysfunction in hypertension. In particular, latest insights in the identification of endothelial-specific microRNAs and their targets are added to the understanding of miRNA significance in hypertension.SummaryThis comprehensive knowledge of the role of miRNAs in endothelial dysfunction and hypertension and of molecular mechanisms proposed for miRNA actions may offer novel diagnostic biomarkers and therapeutic targets for controlling hypertension-associated endothelial dysfunction and other cardiovascular complications.

130 - Scavenging of Reactive Isolevuglandins in Mitochondria Reduces Vascular Oxidative Stress and Attenuates Hypertension

Free radical oxidation of arachidonic acid produces highly reactive isolevuglandins (isoLG) which causes mitochondrial dysfunction by opening of the mitochondrial permeability transition pore (mPTP). Inhibition of the mPTP regulatory subunit cyclophilin D reduces isoLG-induced mitochondrial dysfunction (Free Radic Biol Med 2010;49:567-79). We found that depletion of cyclophilin D diminishes mitochondrial O 2 ●– , improves vascular relaxation and reduces hypertension (Hypertension 2016;67:1218-27). We hypothesized that hypertension is associated with accumulation of mitochondrial isoLG and mitochondria-targeted isoLG scavenger reduces vascular oxidative stress and attenuates hypertension. To test this hypothesis we developed mitochondria-targeted isoLG scavenger 4-(aminomethyl)-3-hydroxyphenoxy) butyl)triphenyl-phosphonium (mito2HOBA) by conjugation of lipophilic triphenylmethylphosphonium cation to 2-hydroxybenzylamine (2HOBA). Mito2HOBA is a water soluble compound which was well tolerated by cultured human aortic endothelial cells (HAECs) and by mice receiving it in drinking water. It was found that mito2HOBA (50 nM) inhibited mitochondrial O 2 ●– production (MitoSOX/HPLC) and prevented cardiolipin oxidation (LS-MS) in HEACs incubated with TNFα+Angiotensin II while untargeted analog 2HOBA (50 nM) was not effective. The functional role of mitochondrial isoLG was tested in vivo using angiotensin II model of hypertension. C57Bl/6J mice were infused with angiotensin II (0.7 mg/kg/day) or saline (Sham) and received mito2HOBA in the drinking water (0.1 g/L). It was found that mito2HOBA diminished angiotensin II-induced hypertension. Hypertension was associated with increased formation of mitochondrial isoLG measured by Western blot analysis of heart mitochondria using the anti-isoLG D11 scfv antibody and 2-fold decrease in kidney ATP. mito2HOBA reduced accumulation of isoLG adducts in the heart mitochondria and prevented drop in kidney ATP in angiotensin II-infused mice. Decrease of NO is a hallmark of endothelial dysfunction in hypertension due to vascular oxidative stress. We examined vascular oxidative stress by measurements of aortic O 2 ●– using fluorescent O 2 ●– probe DHE and HPLC, and analysis of endothelial NO using Electron Spin Resonance and specific NO spin trap Fe(DETC) 2 . It was found that mito2HOBA reduced vascular O 2 ●– in angiotensin II-infused mice and preserved endothelial NO. These data support the role of mitochondrial oxidative stress and mitochondrial isoLG in endothelial dysfunction and hypertension. We conclude that scavenging of mitochondrial isoLG may have therapeutic potential in cardiovascular disease.