Endothelial Dysfunction In Hypertension Research Articles

The Role of Vascular Endothelial Dysfunction in Hypertension With Hearing Loss

Hypertension can cause hearing loss, but there is no clear definition of the mechanism(s) involved. The study aimed to explore the role of vascular endothelial dysfunction in hypertension with hearing loss. Patients with hypertension were divided into two groups based on hearing loss. Pure tone audiometry (PTA) and endothelial function testing were performed. A total of 216 (432 ears) hypertensive patients were divided into hypertension with hearing loss group (n = 104) and hypertension without hearing loss group (n = 112). The vascular endothelial biomarkers, ET-1 (endothelin-1) and vWF (von Willebrand factor) were significantly higher ( P < .05) in the hypertension with hearing loss group. RHI (reactive hyperemia index), ET-1, and vWF were the factors related to hearing loss. The area under the receiver operating characteristic (ROC) curve (AUC) of RHI in the diagnosis of hypertension with hearing loss was .652 (95% CI .552-.751, P = .005), and the Youden index was 26.2%. The AUC of ET-1 was .706 (95% CI .612-.799, P = .001), and the Youden index was 38.9%. The AUC of vWF was .617 (95% CI .512-.721, P = .003), and the Youden index was 28.1%. Vascular endothelial dysfunction may play a role in the pathogenesis of hypertension with hearing loss.

Lactobacillus and Allobaculum mediates the improvement of vascular endothelial dysfunction during hypertension with TaohongSiwu decoction combined with Dubosiella newyorkensis

BackgroundPrevious study confirmed that both TaohongSiwu decoction (THSWD) and Dubosiella newyorkensis improved hypertension-induced endothelial dysfunction. However, the mechanism of THSWD combined with Dubosiella newyorkensis remains unclear. Purpose: We aimed to investigate the microecological mechanism underlying the THSWD combined with Dubosiella newyorkensis for the prevention of hypertensive vascular endothelial dysfunction. MethodsEight percent high-salt diet was applied to induce hypertension in a mouse model for 4 weeks. THSWD, Dubosiella newyorkensis and THSWD combined with Dubosiella newyorkensis were used to intervene in the model mice to observe the changes of systolic blood pressure (SBP), body weight, blood routine, endothelial function, gut contents microbiota and bile acid metabolites. ResultsResults revealed that THSWD combined with Dubosiella newyorkensis significantly restored blood pressure and regulated body weight, and markedly downregulating serum and vascular levels of endothelin-1 (ET-1), thrombin regulatory protein (TM), vascular hemophilia factor (vWF) and vascular endothelial growth factor (VEGF), and upregulating nitric oxide (NO) levels compared with the model group. Notably, It altered the diversity and community structure of gut contents microbiota in mice. Lactobacillus and Allobaculum was enormously up-regulated at the genus level. Serum bile acid differential metabolites cholic acid and chenodeoxycholic acid were markedly altered. Futhermore, there was a close relationship between Lactobacillus, Allobaculum and endothelial function indexes in mice. ConclusionLactobacillus and Allobaculum play important roles in the prevention of vascular endothelial dysfunction in hypertension during the THSWD combined with Dubosiella newyorkensis.

Interference of MDM2 attenuates vascular endothelial dysfunction in hypertension partly through blocking Notch1/NLRP3 inflammasome pathway

BackgroundHypertension is a life-threatening disease mainly featured as vascular endothelial dysfunction. This study aims to explore the regulatory role of murine double minute 2 (MDM2) in hypertension and vascular damage. MethodsMice were infused with angiotensin II (AngII) to establish a hypertension mouse model in vivo and AngII-stimulated HUVECs were constructed to simulate the damage of vascular endothelial cells in hypertension in vitro. The plasmids targeting to MDM2 was injected to mice or transfected to HUVECs. qRT-PCR and western blot were performed to detect corresponding gene expression in mice aorta. Blood pressure was measured. H&E and Masson staining were conducted to evaluate histological changes of aorta. Responses to the acetylcholine (ACh) and sodium nitroprusside (SNP) were assessed in aorta. ZO-1 expression and cell apoptosis were detected by immunofluorescence and TUNEL, respectively. Network formation ability was determined employing a tube formation. ResultsMDM2 was upregulated in hypertensive mice. Knockdown of MDM2 inhibited AngII-induced high BP, histological damage, vascular relaxation to Ach, and promoted the levels of p-eNOS and ZO-1 in the aorta in hypertensive mice. MDM2 knockdown inactivated Notch1 signaling and NLRP3 inflammasome, while the inhibitory effect of MDM2 knockdown on NLRP3 inflammasome activation was partly restored by the activation of Notch1. Furthermore, knockdown of MDM2 relieved AngII-induced endothelial dysfunction in HUVECs, as well as suppressing AngII-promoted cell apoptosis. Whereas, the impacts generated by MDM2 knockdown were partly weakened by the activation of Notch1 signaling or NLRP3 inflammasome. ConclusionIn summary, knockdown of MDM2 can attenuate vascular endothelial dysfunction in hypertension, which may be achieved through inhibiting the activation of Notch1 and NLRP3 inflammasome.

Hypertension and COVID-19 — current state and prospects

New coronavirus disease (COVID-19) caused by SARS-CoV-2 is associated with a high mortality rate and is a major public health problem worldwide. In publications from the early months of the COVID-19 pandemic, the authors reported that hypertension (HTN) is associated with higher susceptibility to SARS-CoV-2 infection, severe disease, and increased mortality associated with COVID-19. The risk of more severe clinical manifestations of COVID-19 is higher in men and increases dramatically with age. However, according to the results of multivariate analyses with the inclusion of data on age, risk factors (RF) of cardiovascular diseases (CVD), diabetes mellitus, the independent role of HTN in the development and outcome of COVID-19 was not confirmed, while age turned out to be the most significant factor. The authors made the conclusion that HTN may not play an independent role in SARS-CoV-2 infection and the course of COVID-19, and the formation of adverse outcomes is influenced by old age. However, age-related changes include accumulated chronic diseases, their RF, target organ damage etc. Morphofunctional changes caused by a long course of HTN, the development of associated clinical conditions can increase the susceptibility of the cardiovascular system to the damaging effects of SARS-CoV-2, as well as contribute to the formation of adverse outcomes of COVID-19. In addition, diabetes mellitus, obesity, and other metabolic disorders associated with HTN negatively contribute to the course of COVID-19 and the risk of mortality. A more severe course of COVID-19 in HTN patients, especially the elderly, may be facilitated by the mechanisms of cellular and immune inflammation common in these diseases. The endothelial monolayer plays an important role. Endothelial injury and endothelial dysfunction in HTN and endothelitis in COVID-19 may reinforce each other, increasing the likelihood of cardiovascular events in patients with COVID-19. An important pathogenetic mechanism of HTN — the renin-angiotensin- aldosterone system (RAAS) activation — plays a significant role in the genesis of COVID-19. Angiotensin-converting enzyme 2 (ACE) is a key receptor for SARS-CoV-2 entry into human cells, providing a link between COVID-19 and RAAS. In this regard, it was expected that ACE inhibitors and angiotensin II receptor blockers (ARB), which modulate the RAAS, may increase the risk of SARS-CoV-2 infection and worsen outcomes in COVID-19. However, in further experimental and clinical studies, these assumptions were not confirmed. Moreover, currently international experts strongly recommend that ACE inhibitors or ARB be continued in HTN patients with COVID-19, as they protect against cardiovascular complications and improve prognosis. Observations have shown that COVID-19 significantly increases the likelihood of developing HTN, acute coronary syndrome, cardiac arrhythmias, right ventricular dysfunction, myocardial fibrosis, heart failure, and also increases the risk of death from CVD. Further clinical and long-term prospective studies are needed to evaluate the role of past COVID-19 as a RF for CVD and mortality.

Abstract P231: Lipoprotein Lipase Activation Is A Novel Anti-contractile Mechanism That Is Both Endothelium-dependent And Independent.

Risk factors such as hypertriglyceridemia and hypercholesterolemia are commonly attributed to the pathogenesis of atherosclerosis, however, lipoprotein metabolism is also associated with end organ damage and cardiovascular events in hypertensive patients. Lipoprotein lipase (LPL) is an important hydrolase for lipoprotein catabolism. Previous work from our lab has shown that LPL activator, NO-1886 (Ibrolipim), significantly decreased vascular contraction. Physiologically, endothelial function limits contractility and endothelial dysfunction is a hallmark of hypertension. Therefore, we hypothesized that LPL activation would cause endothelial-dependent hypocontractility. To test this hypothesis, mesenteric resistance arteries (MRA) were isolated from male Fischer 344 rats at 3 months of age (n=4-12) and mounted onto a wire myograph. Phenylephrine (PE) concentration-response curves were performed with and without LPL activator, NO-1886 (30 min). Some MRA were denuded of their endothelium or incubated with inhibitors of endothelium-dependent vasodilation. As expected, activating LPL exerted a significant anti-contractile effect in a concentration-dependent manner [KCl (%), Veh: 125±3 vs. NO-1886 (1 uM): 116.0±17 vs. NO-1886 (10 uM): 108±9* vs. NO-1886 (50 uM): 55±4* vs. NO-1886 (100 uM): 29±5*, *p<0.05 vs. Veh]. However, contrary to our hypothesis, denudation only partially restored contraction [KCl (%),Veh: 125±3 vs. NO-1886 (50 uM): 55±4* vs. NO-1886+denuded: 76±4* # , *p<0.05 vs. Veh, # p<0.05 vs. NO-1886]. This suggests that there is both an endothelium-dependent and -independent mechanism by which LPL limits contractility. Endothelial-dependent hypocontractility was found to be mediated by nitric oxide synthase [KCl (%),Veh: 125±3 vs. NO-1886 (50 uM): 55±4 vs. NO-1886+L-NAME (100 uM): 90±5* # , *p<0.05 vs. Veh, # p<0.05 vs. NO-1886]. Endothelium-independent mechanisms by which NO-1886 causes hypocontractility have yet been clarified (data not shown). Overall, this suggests that LPL has an important physiological role in controlling vascular contraction through both endothelial-dependent and -independent means and loss of LPL activity could be a novel mechanism of endothelial dysfunction in hypertension.

Endocan as a marker of endothelial dysfunction in hypertension: a systematic review and meta-analysis.

Hypertension is one of the foremost risk factors for cardiovascular disease and a significant cause of death worldwide. Importantly, endothelial dysfunction (ED) is one of the primary manifestations that may precede the development of hypertension. Endocan is a novel endothelial dysfunction and inflammation biomarker secreted from endothelial cells. Whether endocan may serve as a biomarker of hypertension is currently debated. This systematic review and meta-analysis aimed at linking endocan to ED in hypertensive patients. International databases, including PubMed, Scopus, Embase, and Web of Science, were systematically searched for studies investigating Endocan serum or plasma levels in hypertensive patients and healthy controls. Random effect meta-analysis was performed to calculate the standardized mean difference (SMD) and 95% confidence interval (CI). A total of 20 studies assessing the association between endocan levels and hypertension were included in which 3130 individuals with a mean age of 50.48 ± 8.45 years were assessed. Hypertensive patients presented with higher circulating endocan levels (SMD 0.91, 95% CI 0.44-1.38, p-value < 0.01) compared with healthy controls. Interestingly, our data demonstrated that removing three studies assessing endocan levels in hypertensive patients with different comorbidities or special populations resulted in the same statistically higher endocan levels (SMD 1.16, 95% CI 0.66-1.65, p-value < 0.01). Overall, this systematic review and meta-analysis indicated that in hypertensive patients circulating endocan levels are significantly elevated. Thus, suggesting endocan as an easy-to-use biomarker to detect ED in hypertension. Despite this, more research is warranted to address this potential ability specifically.

Network pharmacology-based approach uncovers the pharmacodynamic components and mechanism of Fructus Tribuli for improving endothelial dysfunction in hypertension

Ethnopharmacological relevanceFructus Tribuli (FT), a traditional Chinese medicinal herbal, has been used for the clinical treatment of cardiovascular diseases for many years and affects vascular endothelial dysfunction (ED) in patients with hypertension. Aim of the studyThis study aimed to demonstrate the pharmacodynamic basis and mechanisms of FT for the treatment of ED. Materials and methodsThe present study used ultra-high-performance liquid chromatography coupled with quadruple-time-of-flight mass spectrometry (UHPLC-Q-TOF/MS) to analyze and identify the chemical components of FT. The active components in blood were determined after the oral administration of FT by comparative analysis to blank plasma. Then, based on the active components in vivo, network pharmacology was performed to predict the potential targets of FT in treating ED. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were also performed, and component-target-pathway networks were constructed. Interactions between the major active components and main targets were verified by molecular docking. Moreover, spontaneously hypertensive rats (SHRs) were divided into the normal, model, valsartan, low-dose FT, medium-dose FT, and high-dose FT experimental groups. In pharmacodynamic verification studies, treatment effects on blood pressure, serum markers (nitric oxide [NO], endothelin-1 [ET-1,], and angiotensin Ⅱ [Ang Ⅱ)]) of ED, and endothelial morphology of the thoracic aorta were evaluated and compared between groups. Finally, the PI3K/AKT/eNOS pathway was analyzed by quantitative real-time polymerase chain reaction (qRT-PCR) and Western blot of the thoracic aorta of rats in each group to detect the mRNA expression of PI3K, AKT, and eNOS and the protein expression of PI3K, AKT, p-AKT, eNOS, and p-eNOS. ResultsA total of 51 chemical components were identified in FT, and 49 active components were identified in rat plasma. Thirteen major active components, 22 main targets, and the PI3K/AKT signaling pathway were screened by network pharmacology. The animal experiment results showed that FT reduced systolic blood pressure and ET-1 and Ang Ⅱ levels and increased NO levels in SHRs to varying degrees. The therapeutic effects were positively correlated with the oral dose of FT. Hematoxylin-eosin (HE) staining confirmed that FT could alleviate the pathological damage of the vascular endothelium. qRT-PCR and Western blot analysis confirmed that up-regulated expression of the PI3K/AKT/eNOS signaling pathway could improve ED. ConclusionsIn this study, the material basis of FT was comprehensively identified, and the protective effect on ED was confirmed. FT had a treatment effect on ED through multi-component, multi-target, and multi-pathways. It also played a role by up-regulating the PI3K/AKT/eNOS signaling pathway.

κ-Opioid Receptors Improve Vascular Endothelial Dysfunction in Salt-Sensitive Hypertension via PI3K/Akt/eNOS Signaling Pathway.

κ-Opioid receptors (κ-OR) are widely used to regulate the activity of the cardiovascular system. To explore the effect and mechanism of κ-OR on salt-sensitive hypertensive endothelial dysfunction, we used Dah1 rats to construct a rat model of salt-sensitive hypertension on a high-salt (HS) diet. Then, the rats were treated with κ-OR activators U50,488H (1.25 mg/kg) and inhibitor nor-BNI (2.0 mg/kg) for 4 weeks, respectively. The rat aortas were collected to detect the contents of NO, ET-1, AngII, NOS, T-AOC, SO, and NT. Protein expression was determined for NOS, Akt, and Caveolin-1. In addition, the vascular endothelial cells were extracted, and the levels of NO, TNF-α, IL-1, IL-6, IL-8, IL-10, p-Akt, and p-eNOS in cell supernatants were detected. In vivo results showed that compared with the HS group, treated with U50,488H promoted rats' vasodilation by increasing the NO content and decreasing ET-1 and AngII contents. U50,488H reduced endothelial cell apoptosis and attenuated vascular, smooth muscle cell and endothelial cell injury. U50,488H also enhanced the rats' response to oxidative stress by increasing the NOS and T-AOC contents. Moreover, U50,488H increased the eNOS, p-eNOS, Akt, and p-AKT expression and decreased the iNOS and Caveolin-1 expression. In vitro results showed that U50,488H promoted NO, IL-10, p-Akt, and p-eNOS levels in endothelial cell supernatants versus the HS group. And U50,488H reduced the adhesion of peripheral blood mononuclear cells and polymorphonuclear neutrophils to endothelial cells and the migration function of polymorphonuclear neutrophils. Our study suggested that κ-OR activation may improve vascular endothelial dysfunction in salt-sensitive hypertensive rats through the PI3K/Akt/eNOS signaling pathway. This may be a potential therapeutic approach in the treatment of hypertension.

Abstract 15824: Microvascular Endothelial Kir2.1 Channels Play Important Role in Flow-Induced Dilation During Hypertension in Humans

Hypertension is associated with decreased endothelial function through reduced contributions of NO. Our recent study discovered that flow-induced generation of NO in resistance arteries of mice and humans, and flow-induced vasodilation (FIV), a hallmark of the endothelial response to flow, critically depend on endothelial inwardly-rectifying K+ channels (Kir2.1). The goal of this study was to establish whether these channels contribute to the impairment of endothelial function in peripheral resistance arteries of humans with hypertension. We measured microvascular function in vessels extracted from subcutaneous fat biopsies isolated from 28 subjects: normotensive (n=19; 30.6±4.4yo; systolic blood pressure-SBP: 115.2±5.7mmHg; diastolic blood pressure-DBP: 75.3±11.3mmHg) and hypertensive (n=9; 50±5.2yo; SBP: 147.1±6.1 mmHg; DBP: 93.1±16.8mmHg). Consistent with previous studies, we find that FIV is impaired in hypertensive subjects as demonstrated by a significant reduction in dilation when compared to the normotensive group. Furthermore, our data suggest that the impairment of FIV in this cohort can be partially attributed to a Kir-dependent vasodilation. Specifically, we show that blocking Kir channels with a specific inhibitor, ML133, or functionally downregulating with endothelial-specific adenoviral vector containing dominant-negative Kir2.1 (dnKir2.1) result in significant decrease in FIV in normotensive subjects and smaller effect in hypertensive patients. The Kir2.1-dependent vasodilation was negatively correlated to both SBP and DBP indicating that Kir contribution reduces as blood pressure increases. In addition, we show that exposing normotensive vessels to acute high pressure, which is known to impair FIV, results in loss of Kir channel contribution, as high-pressure impairs vasodilation in normotensive vessels but no effect is seen when these vessels were incubated with dnKir2.1. Overexpressing WTKir2.1 in endothelium resulted in some improvement in vasodilation in arteries from all participants, with a greater recovery in hypertensive patients. Our data suggest that hypertension-induced suppression of Kir2.1 is an important mechanism underlying endothelial dysfunction in hypertension.

Restoration of Mitochondrial Function Is Essential in the Endothelium-Dependent Vasodilation Induced by Acacetin in Hypertensive Rats.

Mitochondrial dysfunction in the endothelium contributes to the progression of hypertension and plays an obligatory role in modulating vascular tone. Acacetin is a natural flavonoid compound that has been shown to possess multiple beneficial effects, including vasodilatation. However, whether acacetin could improve endothelial function in hypertension by protecting against mitochondria-dependent apoptosis remains to be determined. The mean arterial pressure (MAP) in Wistar Kyoto (WKY) rats, spontaneously hypertensive rats (SHR) administered with acacetin intraperitoneally for 2 h or intragastrically for six weeks were examined. The endothelial injury was evaluated by immunofluorescent staining and a transmission electron microscope (TEM). Vascular tension measurement was performed to assess the protective effect of acacetin on mesenteric arteries. Endothelial injury in the pathogenesis of SHR was modeled in HUVECs treated with Angiotensin II (Ang II). Mitochondria-dependent apoptosis, the opening of Mitochondrial Permeability Transition Pore (mPTP) and mitochondrial dynamics proteins were determined by fluorescence activated cell sorting (FACS), immunofluorescence staining and western blot. Acacetin administered intraperitoneally greatly reduced MAP in SHR by mediating a more pronounced endothelium-dependent dilatation in mesenteric arteries, and the vascular dilatation was reduced remarkably by NG-nitro-L-arginine methyl ester (L-NAME), an inhibitor of NO synthesis. While acacetin administered intragastrically for six weeks had no apparent effect on MAP, it improved the endothelium-dependent dilatation in SHR by activating the AKT/eNOS pathway and protecting against the abnormalities of endothelium and mitochondria. Furthermore, acacetin remarkably inhibited Ang II induced apoptosis by inhibiting the increased expression of Cyclophilin D (CypD), promoted the opening of mPTP, ROS generation, ATP loss and disturbance of dynamin-related protein 1 (DRP1)/optic atrophy1 (OPA1) dynamics in HUVECs. This study suggests that acacetin protected against endothelial dysfunction in hypertension by activating the AKT/eNOS pathway and modulating mitochondrial function by targeting mPTP and DRP1/OPA1-dependent dynamics.

Soluble Epoxide Hydrolase Inhibitor t-AUCB Ameliorates Vascular Endothelial Dysfunction by Influencing the NF-κB/miR-155-5p/eNOS/NO/IκB Cycle in Hypertensive Rats.

Epoxyeicosatrienoic acids (EETs), angiogenic mediators degraded by soluble epoxide hydrolase (sEH), have been shown to exert beneficial effects on the cardiovascular system. The current study assessed the impact of increased EETs with an sEH inhibitor, t-AUCB, on two-kidney-one-clip (2K1C)-induced renovascular endothelial dysfunction, associated with hypertension, in rats. The hypertensive rats exhibited increased systolic blood pressure, reduced renal blood flow, impaired endothelium-dependent relaxation and eNOS phosphorylation in the renal arteries, elevated ROS production in the endothelium of the renal arteries, and decreased EET levels in plasma, the renal arteries, and endothelial cells; however, t-AUCB reversed all the deleterious effects. Moreover, we found that the stimulation of AMPK/UCP2 scavenged ROS and restored endothelial function in the renal arteries of hypertensive rats undergoing therapy with t-AUCB. In addition, we were the first to reveal the potential role of miR-155-5p in the occurrence and development of vascular endothelial dysfunction in hypertension. Importantly, t-AUCB recovered NO bioavailability by regulating the NF-κB/miR-155-5p/eNOS/NO/IκB cycle after the activation of AMPK/UCP2 and the subsequent inhibition of ROS in hypertensive rat renal artery endothelial cells. This study will provide evidence for this additional new mechanism, underlying the benefits of EETs and the related agents against hypertensive vasculopathy.

NLRP3 inflammasome contributes to endothelial dysfunction in angiotensin II-induced hypertension in mice

AimsInflammation is a key feature of endothelial dysfunction induced by angiotensin (Ang) II. The purpose of this study was to explore the role of Nucleotide-binding domain-like receptor protein 3 (NLRP3) inflammasome in endothelial dysfunction in Ang II-induced hypertension. Materials and methodsWe analyzed blood pressure and vascular function of wild-type (WT) and Nlrp3 knockout (Nlrp3−/−) mice, treated with Ang II. In vitro, we mainly tested the endothelial nitric oxide synthase (eNOS) phosphorylation expression of human umbilical vein endothelial cells (HUVECs). Key findingsHere we showed that 14-day Ang II infusion into mice resulted in the elevation of blood pressure, NLRP3 expression, serum interleukin (IL)-1β level, and the decline of endothelium-dependent relaxation function, p-eNOS-Ser1177 expression in aortas. Nlrp3 deficiency reduced Ang II-induced blood pressure elevation and endothelial dysfunction. In vitro, NLRP3 was involved in the effect of Ang II on reducing p-eNOS-Ser1177 expression. Moreover, the direct effect of IL-1β on vascular endothelial injury could be observed in both vivo and vitro. SignificanceOur result demonstrates that the NLRP3 inflammasome is critically involved in the detrimental effects of Ang II on vascular endothelium in hypertension via the activation of IL-1β, placing NLRP3 as a potential target for therapeutic interventions in conditions with endothelial dysfunction in hypertension.

The Association between Serum Resistin Level, Resistin (-420C/G) Single Nucleotide Variant, and Markers of Endothelial Dysfunction, including Salt Taste Preference in Hypertensive Patients.

Background: Resistin action links to conditions such as diabetes, obesity, but its role in hypertension is less well understood. This study aimed to estimate the relationship between resistin (−420G/C) single nucleotide variant (SNV) and markers associated with endothelial dysfunction in hypertension. Methods: The study enrolled 162 hypertensive patients (HT) and 165 non-hypertensive (NHT) patients. Resistin serum concentration was estimated with immuoenzymatic assay. Anthropometric measurements, blood pressure and arterial stiffness index (SI), uric acid (UA) serum concentration, and salty taste preference of normal (NS) or high (HS) were assessed in the study. Genotyping was achieved by polymerase chain reaction-restriction fragment length polymorphism. Results: Resistin concentration and SI do not differ significantly between HT and NHT individuals; UA significantly increased in HT subjects. Resistin, UA, and SI did not differ among particular resistin genotypes in HT, NHT, NS, or HS groups. GG and CG genotypes were more frequent (OR 1.57 (95% CI; 1.01–2.43); p = 0.04) in hypertensive individuals than the NHT group, but less frequent (OR 0.58 (95% CI; 0.37–0.91); p = 0.01) in HS patients compared to NS individuals. Concerning HT patients with different salt preferences, GG + CG genotypes were less frequent (OR 0.50 (95% CI; 0.26–0.97); p = 0.04) in the HS group than in NS individuals. HT carriers of GG and CG genotype have significantly increased UA concentrations compared to the respective NHT subjects. HS individuals carrying GG and CG genotypes have higher SI values than the NS group. Allele G of SNV (−420G/C) adjusted for age, BMI, serum resistin, UA concentration, salt taste preference, SI, and HR values increased the risk of developing hypertensive phenotype 1.8 fold. Conclusions: Resistin SNV (−420G/C) is related to several markers associated with endothelial dysfunction, including salt taste preference in hypertensive patients.

Endothelial Dysfunction in Hypertension: Current Concepts and Clinical Implications.

Endothelium plays a fundamental role in the cardiovascular system, forming an interface between blood and adjacent tissues by regulating the vascular tone through the synthesis of nitric oxide, prostaglandins and other relaxing factors. Endothelial dysfunction is characterized by vasoconstriction, cell proliferation and shifting toward a proinflammatory and prothrombic state. In hypertension endothelial dysfunction may be involved in the initiation and development of vascular inflammation, vascular remodeling, and atherosclerosis and is independently associated with increased cardiovascular risk. Different conditions such as impaired vascular shear stress, inflammation and oxidative stress, activation of the renin angiotensin system have been described as important pathophysiological mechanisms involved in the development of endothelial dysfunction. The release of extracellular vesicles by neighboring cells in the vascular wall has emerged as an important regulator of endothelial function and with potential antihypertensive properties and beneficial effects by counteracting the hypertension mediated organ damage. Furthermore, macrovesicles are emerging as an innovative therapeutic approach for vascular protection, allowing the delivery of bioactive molecules, such as miRNA and drugs interacting with the renin angiotensin system. In this review we summarize the available evidence about the pathophysiological implications of endothelial dysfunction in cardiovascular diseases, focusing on hypertension and its sequelae, and the potential innovative therapeutic strategies targeting the endothelium with the aim to improve vascular function and remodeling.

Down-regulation of AMPK/PPARδ signalling promotes endoplasmic reticulum stress-induced endothelial dysfunction in adult rat offspring exposed to maternal diabetes.

Exposure to maternal diabetes is associated with increased prevalence of hypertension in the offspring. The mechanisms underlying the prenatal programming of hypertension remain unclear. Because endoplasmic reticulum (ER) stress plays a key role in vascular endothelial dysfunction in hypertension, we investigated whether aberrant ER stress causes endothelial dysfunction and high blood pressure in the offspring of dams with diabetes. Pregnant Sprague-Dawley rats were intraperitoneally injected with streptozotocin (35 mg/kg) or citrate buffer at Day 0 of gestation. Compared with control mother offspring (CMO), the diabetic mother offspring (DMO) had higher blood pressure and impaired endothelium-dependent relaxation in mesenteric arteries, accompanied by decreased AMPK phosphorylation and PPARδ expression, increased ER stress markers, and reactive oxygen species (ROS) levels. The inhibition of ER stress reversed these aberrant changes in DMO. Ex vivo treatment of mesenteric arteries with an AMPK agonist (A769662) or a PPARδ agonist (GW1516) improved the impaired EDR in DMO and reversed the tunicamycin-induced ER stress, ROS production, and EDR impairment in mesenteric arteries from CMO. The effects of A769662 were abolished by co-treatment with GSK0660 (PPARδ antagonist), whereas the effects of GW1516 were unaffected by Compound C (AMPK inhibitor). These results suggest an abnormal foetal programming of vascular endothelial function in offspring of rats with maternal diabetes that is associated with increased ER stress, which can be ascribed to down-regulation of AMPK/PPARδ signalling cascade.

C-type natriuretic peptide-induced relaxation through cGMP-dependent protein kinase and SERCA activation is impaired in two kidney-one clip rat aorta

AimsHypertension underlies endothelial dysfunction, and activation of vasorelaxation signaling with low dependence on nitric oxide (NO) represents a good alternative for vascular modulation. C-type natriuretic peptide (CNP) causes relaxation by increasing cyclic guanosine 3′,5′-monophosphate (cGMP) or Gi-protein activation through its natriuretic peptide receptor-B or -C, respectively. We have hypothesized that CNP could exerts its effects and could overcome endothelial dysfunction in two kidney-one clip (2K-1C) hypertensive rat aorta. Here, we investigate the intracellular signaling involved in CNP effects in hypertension. Materials and methodsThe 2K-1C hypertension was induced in male Wistar rats (200 g). CNP-induced vascular relaxation and cGMP production were investigated in rat thoracic aortas. The natriuretic peptide receptor-B and -C localization was evaluated by immunofluorescence. Calcium mobilization was assessed in endothelial cells from rat aortas. Key findingsCNP induced similar relaxation in normotensive and 2K-1C hypertensive rat aortas, which increased after endothelium removal. CNP-induced relaxation involved natriuretic peptide receptor-B and -C activation in 2K-1C rats. Nitric oxide synthase (NOS) and soluble guanylyl cyclase (sGC) counter-regulated CNP-particulate GC (pGC) activation in aortas. CNP reduced endothelial calcium and increased cGMP production, which was lower in 2K-1C. CNP-induced cGMP-dependent protein kinase (PKG) and sarcoplasmic/endoplasmic reticulum Ca2+-ATPase (SERCA) activation was impaired in 2K-1C rat aorta. SignificanceOur results indicated CNP triggered relaxation through its natriuretic peptide receptor-B and -C in 2K-1C rat aortas, and that CNP-induced relaxation overcomes endothelial dysfunction in hypertension. In addition, NOS and sGC activities counter-regulate CNP-pGC activation to induce vascular relaxation.

Sinapine Thiocyanate Ameliorates Vascular Endothelial Dysfunction in Hypertension by Inhibiting Activation of the NLRP3 Inflammasome.

The increase of blood pressure is accompanied by the changes in the morphology and function of vascular endothelial cells. Vascular endothelial injury and hypertension actually interact as both cause and effect. A large number of studies have proved that inflammation plays a significant role in the occurrence and development of hypertension, but the potential mechanism between inflammation and hypertensive endothelial injury is still ambiguous. The purpose of this study was to explore the association between the activation of NLRP3 inflammasome and hypertensive endothelial damage, and to demonstrate the protective effect of sinapine thiocyanate (ST) on endothelia in hypertension. The expression of NLRP3 gene was silenced by tail vein injection of adeno-associated virus (AAVs) in spontaneously hypertensive rats (SHRs), indicating that activation of NLRP3 inflammasome accelerated hypertensive endothelial injury. ST not only protected vascular endothelial function in SHRs by inhibiting the activation of NLRP3 inflammasome and the expression of related inflammatory mediators, but also improved AngII-induced huvec injury. In summary, our results show that alleviative NLRP3 inflammasome activation attenuates hypertensive endothelial damage and ST ameliorates vascular endothelial dysfunction in hypertension via inhibiting activation of the NLRP3 inflammasome.

Circulating senescent angiogenic T cells are linked with endothelial dysfunction and systemic inflammation in hypertension.

Objective:Angiogenic T cells (Tang cells), a recently discovered T-cell subset, have been reported involved in the repair of endothelial injury. The purpose of this study was to explore the correlation of immunologic senescence and pro-inflammatory capacity of Tang cells with endothelial dysfunction in hypertensive patients.Methods:Immunological characteristics of Tang cells (CD3+CD31+CXCR4+) from hypertensive patients with or without endothelial dysfunction were elucidated by surface immunophenotyping and intracellular cytokine staining. Endothelial function was measured by flow-mediated dilation (FMD).Results:The frequency of CD28null subset in CD4+ Tang cells was notably elevated in hypertensive patients with endothelial dysfunction, which was negatively associated with FMD. The high frequency of CD28nullCD4+ Tang cells was an independent risk factor of endothelial dysfunction with good diagnostic performance in ROC curve analysis. Immunophenotyping revealed that this specific subset of Tang cells exhibited senescent profile and has low hTERT expression. CD28nullCD4+ Tang cells produced high levels of inflammatory cytokines, IL-6, IFN-γ and TNF-α, and significantly correlated with the systemic inflammation in hypertensive patients with endothelial dysfunction.Conclusion:Collectively, our findings demonstrate for the first time that CD28null subset in CD4+ Tang cells with senescent and pro-inflammatory phenotype is dependently correlated with impaired FMD and systemic inflammation, which might contribute to the immunopathologic mechanism of endothelial dysfunction. Identification of a pathogenic CD4+ Tang-cell subset lacking CD28 may offer opportunities for the evaluation and management of endothelial dysfunction in hypertension.

Combination therapy with pemafibrate (K-877) and pitavastatin improves vascular endothelial dysfunction in dahl/salt-sensitive rats fed a high-salt and high-fat diet

BackgroundStatins suppress the progression of atherosclerosis by reducing low-density lipoprotein (LDL) cholesterol levels. Pemafibrate (K-877), a novel selective peroxisome proliferator-activated receptor α modulator, is expected to reduce residual risk factors including high triglycerides (TGs) and low high-density lipoprotein (HDL) cholesterol during statin treatment. However, it is not known if statin therapy with add-on pemafibrate improves the progression of atherosclerosis. The aim of this study was to assess the effect of combination therapy with pitavastatin and pemafibrate on lipid profiles and endothelial dysfunction in hypertension and insulin resistance model rats.MethodsSeven-week-old male Dahl salt-sensitive (DS) rats were divided into the following five treatment groups (normal diet (ND) plus vehicle, high-salt and high-fat diet (HD) plus vehicle, HD plus pitavastatin (0.3 mg/kg/day), HD plus pemafibrate (K-877) (0.5 mg/kg/day), and HD plus combination of pitavastatin and pemafibrate) and treated for 12 weeks. At 19 weeks, endothelium-dependent relaxation of the thoracic aorta in response to acetylcholine was evaluated.ResultsAfter feeding for 12 weeks, systolic blood pressure and plasma levels of total cholesterol were significantly higher in the HD-vehicle group compared with the ND-vehicle group. Combination therapy with pitavastatin and pemafibrate significantly reduced systolic blood pressure, TG levels, including total, chylomicron (CM), very LDL (VLDL), HDL-TG, and cholesterol levels, including total, CM, VLDL, and LDL-cholesterol, compared with vehicle treatment. Acetylcholine caused concentration-dependent relaxation of thoracic aorta rings that were pre-contracted with phenylephrine in all rats. Relaxation rates in the HD-vehicle group were significantly lower compared with the ND-vehicle group. Relaxation rates in the HD-combination of pitavastatin and pemafibrate group significantly increased compared with the HD-vehicle group, although neither medication alone ameliorated relaxation rates significantly. Western blotting experiments showed increased phosphorylated endothelial nitric oxide synthase protein expression in aortas from rats in the HD-pemafibrate group and the HD-combination group compared with the HD-vehicle group. However, the expression levels did not respond significantly to pitavastatin alone.ConclusionsCombination therapy with pitavastatin and pemafibrate improved lipid profiles and endothelial dysfunction in hypertension and insulin resistance model rats. Pemafibrate as an add-on strategy to statins may be useful for preventing atherosclerosis progression.

Calcitriol inhibits COX-1 and COX-2 expressions of renal vasculature in hypertension: Reactive oxygen species involved?

ABSTRACT Vitamin D modulates about 3% human gene transcription besides the classical action on calcium/phosphorus homeostasis. The blood pressure-lowing and other protective action on cardiovascular disease have been reported. The present study aims to examine whether COX-1 and COX-2 were implicated in endothelial dysfunction in hypertension and calcitriol, an active form of vitamin D preserved endothelial function through regulating COX expression. Isometric study demonstrated the impaired endothelium-dependent relaxation (EDR) in renal arteries from spontaneously hypertensive rats were reversed by 12 h-calcitriol treatment and COX-1 and COX-2 inhibitors. Combined uses of COX-1 and COX-2 inhibitor induced more improved relaxations. Exaggerated expressions of COX-1 and COX-2 in renal artery from SHR were inhibited by 12 h-administration of calcitriol, NADPH oxidase inhibitor DPI, or reactive oxygen species (ROS) scavenger tempol. Furthermore, in normotensive WKY rats, calcitriol prevents against the blunted EDR in renal arteries by 12 h-Ang II exposure, with similar improvements by COX-1 and COX-2 inhibitors. Accordingly, increased COX-1 and COX-2 expressions by Ang II exposure were corrected by losartan, DPI, or tempol. Studies on human renal artery also revealed the beneficial action of calcitriol is mediated by suppressing COX-1 and COX-2 expressions, dependent on vitamin D receptor (VDR) activation. Taken together, our findings showed that COX-1 and COX-2 are positively involved in the renovascular dysfunction in hypertension and via VDR, calcitriol benefits renovasular function by suppressing COX-1 and COX-2 expressions. Furthermore, ROS is involved in the COX-1 and COX-2 up-regulations of renal arteries, maybe serving as a mediator in the inhibitory action of calcitriol on COX expression.