Target For Treatment Of Hypertension Research Articles

Apelin-13's Actions in Controlling Hypertension-Related Cardiac Hypertrophy and the Expressions of Inflammatory Cytokines.

As a key molecule for improving cardiovascular diseases, Apelin-13 was surveyed in this work to explain its actions in controlling inflammation, pyroptosis, and myocardial hypertrophy. First, mouse models with myocardial hypertrophy were established. Then, assessments were made on the pathological variation in the heart of mouse, on the cardiac functions, as well as on the expressions of cardiac hypertrophy markers (β-MHC, ANP, and BNP), inflammatory factors (TNF-α, COX2, IL-6, ICAM-1, and VCAM-1), myocardial cell pyroptosis markers (NLRP3, ASC, c-caspase-1, and GSDMD-N), and Hippo pathway proteins (p-YAP, YAP, LATS1, and p-LATS1) by HE staining, echocardiography scanning, and western blot tests separately. The expressions of such inflammatory factors as in myocardial tissue were acquired by ELISA. After inducing the phenotype of H9c2 cell hypertrophy by noradrenaline, we used CCK-8 kits to know about the activity of H9c2 cells treated with Apelin-13, and performed ɑ-actinin staining to measure the changes in volumes of such cells. As unraveled through this work, Apelin-13 refrained the activation of the Hippo pathway, which in turn attenuated the hypertrophy, inflammation, and pyroptosis of myocardial tissue and H9c2 cells. Hence, Apelin-13 can be considered as a target for hypertension treatment.

Abstract P210: IDENTIFICATION OF ALAMANDINE-(1-5) AS A NEW ANTI-HYPERTENSIVE PEPTIDE OF THE RENIN-ANGIOTENSIN SYSTEM

It is currently accepted that angiotensin-(1-7) [Ang-(1-7)] and alamandine [Ala 1 -Ang-(1-7)] are members of the counterregulatory axis of the renin-angiotensin system (RAS). Both peptides can undergo hydrolysis by angiotensin-converting enzyme and form Ang-(1-5) and Alamandine-(1-5), respectively. Recently, we have shown that Alamandine-(1-5) is present in human and mice circulation. Here, we evaluated the cardiovascular effects induced by intravenous (i.v.) administration of these peptides in conscious normotensive Wistar (n=6 for each peptide) and spontaneously hypertensive rats (SHR) (n=6 for each peptide). After a period of one hour for stabilization of the cardiovascular parameters, Alamandine-(1-5) or Ang-(1-5) were injected at a dose of 3µg/ 100g of b.w. A similar volume (0.1 ml/ 100g b.w.) of sterile saline was injected into SHR and Wistar rats for control. Alamandine-(1-5) injection produced a progressive decrease in systolic blood pressure (SBP, SHR, reaching -33±3.0 mmHg six hours after injection (Baseline SBP: 208±8 mmHg before and 175±10 mmHg, six hours after the injection). In contrast, SBP did not significantly change after the administration of Ang-(1-5) (Baseline SBP: 198±13 mmHg before and 199±8 mmHg six hours after injection). There was no significant change in heart rate (HR) in SHR after Alamandine-(1-5) (Baseline HR: 342±14 beats/min before and 341±18.8 beats/min after six hours) or after Ang-(1-5) (Baseline HR: 333±18 beats/min before and 326±19 beats/min after six hours). Alamandine-(1-5) injection in Wistar rats produced only small changes in BP (Baseline SBP: 109±10 mmHg before injection and 99±11 mmHg six hours after injection, p<0.05). No differences were observed for Ang-(1-5) injection in Wistar rats (Baseline SBP: 118±8 mmHg before injection and 115±9 mmHg six hours after injection) or in HR for Alamandine-(1-5) or Ang-(1-5). Saline injection did not change BP or HR in SHR or in Wistar rats. These results show that Alamandine-(1-5), but not Ang-(1-5), triggers a long-lasting fall in BP in hypertensive animals. These data indicate that we have identified a new vasodilatory peptide of the RAS, increasing our understanding of the complexity of this system and opening a possibility for future development of a new pharmacological target for hypertension treatment.

Irisin attenuates vascular remodeling in hypertensive mice induced by Ang II by suppressing Ca2+-dependent endoplasmic reticulum stress in VSMCs.

Vascular remodeling plays a vital role in hypertensive diseases and is an important target for hypertension treatment. Irisin, a newly discovered myokine and adipokine, has been found to have beneficial effects on various cardiovascular diseases. However, the pharmacological effect of irisin in antagonizing hypertension-induced vascular remodeling is not well understood. In the present study, we investigated the protection and mechanisms of irisin against hypertension and vascular remodeling induced by angiotensin II (Ang II). Adult male mice of wild-type, FNDC5 (irisin-precursor) knockout, and FNDC5 overexpression were used to develop hypertension by challenging them with Ang II subcutaneously in the back using a microosmotic pump for 4 weeks. Similar to the attenuation of irisin on Ang II-induced VSMCs remodeling, endogenous FNDC5 ablation exacerbated, and exogenous FNDC5 overexpression alleviated Ang II-induced hypertension and vascular remodeling. Aortic RNA sequencing showed that irisin deficiency exacerbated intracellular calcium imbalance and increased vasoconstriction, which was parallel to the deterioration in both ER calcium dysmetabolism and ER stress. FNDC5 overexpression/exogenous irisin supplementation protected VSMCs from Ang II-induced remodeling by improving endoplasmic reticulum (ER) homeostasis. This improvement includes inhibiting Ca2+ release from the ER and promoting the re-absorption of Ca2+ into the ER, thus relieving Ca2+-dependent ER stress. Furthermore, irisin was confirmed to bind to its receptors, αV/β5 integrins, to further activate the AMPK pathway and inhibit the p38 pathway, leading to vasoprotection in Ang II-insulted VSMCs. These results indicate that irisin protects against hypertension and vascular remodeling in Ang II-challenged mice by restoring calcium homeostasis and attenuating ER stress in VSMCs via activating AMPK and suppressing p38 signaling.

Effect of Enzymatic Biotransformation on the Hypotensive Potential of Red Grape Pomace Extract.

Hypertension is a widespread health risk, affecting over a billion people and causing 9 million deaths per year. The Renin-Angiotensin-Aldosterone System (RAAS) is a primary target for hypertension treatment, and it is primarily treated through drugs that inhibit the Angiotensin I-Converting Enzyme (ACE). In addition to pharmacological treatment, various plants are recommended in traditional medicine for blood pressure regulation. This study aimed to produce high-phenolic-content extracts with and without enzymatic assistance from red grape pomace and evaluate their antioxidant capacity and ACE inhibitory potential. The total phenolic content (TPC) was measured, and phenolic identification was performed using HPLC analysis. In addition, the antioxidant capacity and anti-hypertensive potential were determined via in vitro assays. There was no statistical difference in the TPC antioxidant capacity between the extraction methods. Otherwise, when considering the extraction yield, the enzymatic process recovered around 70% more phenolic compounds from the pomace, and the phenolic profile was changed. Enzymatic assistance also significantly increased the ACE inhibitory potential in the grape pomace extract. This study demonstrates the viability of upcycling grape pomace to obtain bioactive compounds and to reduce their environmental impact, and highlights the influence of the enzymatic extraction on the hypotensive potential of the extract.

MicroRNA-31 regulates TNF-α and IL-17A co-induced-endothelial cell apoptosis by repressing E2F6

Vascular endothelial cell (VEC) apoptosis is the fundamental cause of pulmonary arterial hypertension. MicroRNA-31 (MiR-31) is a novel target for hypertension treatment. However, the role and mechanism of miR-31 in the apoptosis of VECs remain unclear. The purpose of this study is to determine whether miR-31 plays an important role in VEC apoptosis as well as the detailed mechanisms involved. We found that pro-inflammatory cytokines IL-17A and TNF-α were highly expressed in serum and aorta, and the expression of miR-31 was significantly increased in aortic intimal tissue from Angiotensin II (AngII)- induced hypertensive mice (WT-AngII) compared with control mice (WT-NC). In vitro, co-stimulation of VECs with IL-17A and TNF-α resulted in increased expression of miR-31 and VEC apoptosis. MiR-31 inhibition strikingly decreased TNF-α and IL-17A co-induced VEC apoptosis. Mechanistically, in IL-17A and TNF-α co-stimulated VECs (co-induced VECs), we found that the activation of the NF-κB signal effectively increased the expression of miR-31. Dual-luciferase reporter gene assay revealed that miR-31 directly targeted and inhibited the expression of the E2F transcription factor 6 (E2F6). The expression of E2F6 was decreased in Co-induced VECs. MiR-31 inhibition significantly alleviated the decreased expression of E2F6 in co-induced VECs. Consistent with the co-stimulated effect of IL-17A and TNF-α on VECs, transfection of siRNA E2F6 induced cell apoptosis without the stimulation of the above cytokines. In conclusion, TNF-α and IL-17A generated in the aortic vascular tissue and serum from Ang II-induced hypertensive mice could trigger VECs apoptosis by the miR-31/E2F6 axis. To sum up, our study suggests that the key factor between cytokine co-stimulation effect and VEC apoptosis was miR-31/E2F6 axis, which was mainly regulated by NF-қB signaling pathway. This gives us a new sight to treat hypertension-associated VR.

PL-4: INSIGHTS INTO MOLECULAR MECHANISMS OF HYPERTENSION FROM HUMAN GENETICS

Identification and investigation of rare patients with extreme forms of high and low blood pressure has led to the identification of specific genes whose mutation results in these outlier phenotypes. These rare mutations converge on genes that mediate or regulate the renal reabsorption of Na-Cl. Mutations that increase or decrease renal salt reabsorption respectively increase or decrease blood pressure. Mutations that cause hypertension include gain of function mutations in subunits of the epithelial Na+ channel (ENaC) and in any of eight genes that cause constitutive activity of ENaC by its stimulation via its major regulator, the mineralocorticoid receptor, the target of aldosterone signaling; these increase salt reabsorption in the distal nephron. Conversely, mutations that cause hypotension include loss of function mutations in ENaC subunits, but also mutations the thiazide-sensitive Na-Cl cotransporter (NCC) or a K+ channel required for cotransporter function that act in the distal convoluted tubule (DCT), or mutations in the Na-K-2Cl cotransporter as well as K+ and Cl- channels expressed in the thick ascending limb of Henle that are required for normal Na-Cl reabsorption in this nephron segment. ENaC, the Na-Cl cotransporter and the Na-K-2Cl cotransporter, as well as the mineralocorticoid receptor are all commonly used targets for treatment of hypertension and/or diuresis. In addition to these genes, genetic studies also identified a previously unrecognized pathway that regulates the balance between renal salt reabsorption and K+ secretion. Mutations in the kinases WNK1 or WNK4, or genes that mediate their degradation via ubiquitylation, CUL3 and KLHL3 cause hypertension with hyperkalemia. Activity of WNK1 and WNK4 stimulates activation of NCC promoting Na-Cl reabsorption in the DCT, reducing Na-Cl- delivery distally, thereby limiting ENaC activity and limiting K+ secretion in the distal nephron. Conversely, hyperkalemia inhibits WNK activity, promoting distal Na-Cl delivery and maximizing K+ secretion. Angiotensin II signaling promotes WNK activity, increasing Na-Cl reabsorption in the DCT and inhibiting K+ secretion, while hyperkalemia appears to inhibit WNK activity, providing distal Na+ delivery that is used to drive K+ secretion. The importance of this pathway is that it can explain the mechanism by which increased dietary K+ lowers blood pressure. Both reduced dietary salt intake and increased dietary K+ can reduce blood pressure in controlled settings, and recent large population studies have shown that increased dietary K+ and reduced Na-Cl intake not only lower blood pressure but reduce the incidence of cardiovascular disease and death.

Uromodulin Regulates Murine Aquaporin-2 Activity via Thick Ascending Limb-Collecting Duct Cross-Talk during Water Deprivation.

Uromodulin, a urinary protein synthesized and secreted from the thick ascending limb (TAL) of the loop of Henle, is associated with hypertension through the activation of sodium reabsorption in the TAL. Uromodulin is a potential target for hypertension treatment via natriuresis. However, its biological function in epithelial cells of the distal nephron segment, particularly the collecting duct, remains unknown. Herein, we examined the regulation of uromodulin production during water deprivation in vivo as well as the effect of uromodulin on the activity of the water channel aquaporin−2 (AQP2) in vitro and in vivo using transgenic mice. Water deprivation upregulated uromodulin production; immunofluorescence experiments revealed uromodulin adhesion on the apical surface of the collecting duct. Furthermore, the activation of AQP2 was attenuated in mice lacking uromodulin. Uromodulin enhanced the phosphorylation and apical trafficking of AQP2 in mouse collecting duct cells treated with the vasopressin analog dDAVP. The uromodulin-induced apical trafficking of AQP2 was attenuated via endocytosis inhibitor treatment, suggesting that uromodulin activates AQP2 through the suppression of endocytosis. This study provides novel insights into the cross−talk between TAL and the collecting duct, and indicates that the modulation of uromodulin is a promising approach for diuresis and hypertension treatment.

Endothelial TRPV4-eNOS coupling as a vital therapy target for treatment of hypertension.

Reduced NO levels and activity are signs of endothelial dysfunction, which is important in mediating BP changes. Previously, we demonstrated that transient receptor potential channel V4 (TRPV4) could form a functional complex with other proteins to mediate vasodilation in endothelial cells (ECs). But how TRPV4 interacts with the NO pathway in larger arteries requires further exploration. We used single-cell RNA-sequencing to find the CD106+ TRPV4high NOS3high ECs. The TRPV4-eNOS interaction was verified by co-immunoprecipitation and immuno-FRET, and their binding site was found by site-directed mutagenesis. Endothelium-specific TRPV4 knockout (TRPV4EC-/- ) mice were used to study the effect of the TRPV4-eNOS interaction on BP. A small molecule, JNc-463, was designed through molecular docking technology. We uncovered CD106+ TRPV4high NOS3high ECs in the mouse aorta, which could regulate vasodilation via a TRPV4-eNOS interaction, and were essential to regulate BP. The TRPV4-eNOS interaction markedly decreased during the process of hypertension. We further attempted to identify molecules involved in the TRPV4-eNOS interaction and developed a small-molecule drug, JNc-463, which could increase the TRPV4-eNOS interaction to enhance vasodilation and exert antihypertensive effects in mice. This is the first study integrating single-cell RNA-Seq, single-cell functional study and drug screening in aorta. We identified a subpopulation of CD106+ TRPV4high NOS3high ECs, in which an impaired TRPV4-eNOS interaction was important in the progress of hypertension, and we designed a small molecule, JNc-463, to improve the impaired TRPV4-eNOS interaction in hypertension.

Investigation of angiotensin-I-converting enzyme (ACE) inhibitory tri-peptides: a combination of 3D-QSAR and molecular docking simulations.

Angiotensin-I-converting enzyme (ACE) is a key enzyme in the regulation of peripheral blood pressure and electrolyte homeostasis. Therefore, ACE is considered as a promising target for treatment of hypertension. In the present work, in order to investigate the binding interactions between ACE and tri-peptides, three-dimensional quantitative structure–activity relationship (3D-QSAR) models using comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) methods were developed. Three different alignment methods (template ligand-based, docking-based, and common scaffold-based) were employed to construct reliable 3D-QSAR models. Statistical parameters derived from the QSAR models indicated that the template ligand-based CoMFA (Rcv2 = 0.761, Rpred2 = 0.6257) and CoMSIA (Rcv2 = 0.757, Rpred2 = 0.6969) models were better than the other alignment-based models. In addition, molecular docking studies were carried out to predict the binding modes of the peptides to ACE. The peptide–enzyme interactions were consistent with the derived 3D contour maps. Overall, the insights gained from this study would offer theoretical references for understanding the mechanism of action of tri-peptides when binding to ACE and aid in the design of more potent tri-peptides.

Expression of lncRNA TUG1 in hypertensive patients and its relationship with change state of an illness.

To investigate the expression of LncRNA TUG1 in hypertensive patients and its relationship with the change state of illness. A prospective analysis was carried out. Eighty-two patients with hypertension admitted to our hospital from March 2016 to February 2019 were regarded as a research group, and 79 healthy people admitted to our hospital during the same period were regarded as a control group. The serum LncRNA TUG1, platelet activating factor (PAF), endothelin-1 (ET-1), serum tumor necrosis factor-α (TNF-α), high sensitive C-reactive protein (hsCRP), and the relationship between the expression of LncRNA TUG1 and the clinicopathological characteristics of patients with hypertension in the two groups were detected, and finally, the risk factors of hypertension were analyzed. The expression levels of LncRNA TUG1, PAF, ET-1, TNF-α, and hsCRP in the serum of patients in research group were significantly higher than those in control group (p<0.05). LncRNA TUG1 has a positive correlation with the severity of an illness of hypertensive patients (r=0.881, p<0.001), and also has a positive correlation with the expression levels of PAF, ET-1, TNF-α, and hsCRP (r=0.735, p<0.001; r=0.756, p<0.001; r=0.712, p<0.05; r=0.723, p<0.05). The expression of LncRNA TUG1 in the serum of patients with hypertension was related to hypertension mode, severity of disease, hyperlipidemia, and obesity (p<0.05). Obesity (OR: 3.469, 95% CI: 2.175-4.095), drinking (OR: 3.677, 95% CI: 1.695-4.892), hyperlipidemia (OR: 3.374, 95% CI: 1.759-6.988), and the high expression of TUG1 (OR: 2.693, 95% CI: 1.679-7.472) are independent risk factors for the attack of hypertension. LncRNA TUG1 is highly expressed in the serum of hypertensive patients and it is closely related to the progression of hypertension. Also, it may be one of the independent risk factors for hypertension and a new molecular target for hypertension treatment.

Computational and Pharmacogenomic Insights on Hypertension Treatment: Rational Drug Design and Optimization Strategies.

Hypertension is a prevalent cardiovascular complication caused by genetic and nongenetic factors. Blood pressure (BP) management is difficult because most patients become resistant to monotherapy soon after treatment initiation. Although many antihypertensive drugs are available, some patients do not respond to multiple drugs. Identification of personalized antihypertensive treatments is a key for better BP management. This review aimed to elucidate aspects of rational drug design and other methods to develop better hypertension management. Among hypertension-related signaling mechanisms, the renin-angiotensin-aldosterone system is the leading genetic target for hypertension treatment. Identifying a single drug that acts on multiple targets is an emerging strategy for hypertension treatment, and could be achieved by discovering new drug targets with less mutated and highly conserved regions. Extending pharmacogenomics research to include patients with hypertension receiving multiple antihypertensive drugs could help identify the genetic markers of hypertension. However, available evidence on the role of pharmacogenomics in hypertension is limited and primarily focused on candidate genes. Studies on hypertension pharmacogenomics aim to identify the genetic causes of response variations to antihypertensive drugs. Genetic association studies have identified single nucleotide polymorphisms affecting drug responses. To understand how genetic traits alter drug responses, computational screening of mutagenesis can be utilized to observe drug response variations at the protein level, which can help identify new inhibitors and drug targets to manage hypertension. Rational drug design facilitates the discovery and design of potent inhibitors. However, further research and clinical validation are required before novel inhibitors can be clinically used as antihypertensive therapies.

Clinical Implications

Clinical Implications

MiR-431-5p Knockdown Protects Against Angiotensin II-Induced Hypertension and Vascular Injury.

Vascular injury is an early manifestation in hypertension and a cause of end-organ damage. MicroRNAs play an important role in cardiovascular disease, but their implication in vascular injury in hypertension remains unclear. This study revealed using an unbiased approach, microRNA and mRNA sequencing with molecular interaction analysis, a microRNA-transcription factor coregulatory network involved in vascular injury in mice made hypertensive by 14-day Ang II (angiotensin II) infusion. A candidate gene approach identified upregulated miR-431-5p encoded in the conserved 12qF1 (14q32 in humans) microRNA cluster, whose expression correlated with blood pressure, and which has been shown to be upregulated in human atherosclerosis, as a potential key regulator in Ang II-induced vascular injury. Gain- and loss-of-function in human vascular smooth muscle cells demonstrated that miR-431-5p regulates in part gene expression by targeting ETS homologous factor. In vivo miR-431-5p knockdown delayed Ang II-induced blood pressure elevation and reduced vascular injury in mice, which demonstrated its potential as a target for treatment of hypertension and vascular injury.

TRPV1 Exaggerates Cardiovascular Responses to Physical Exercise in Normotensive but Not in Hypertensive Rats

IntroductionThe transient receptor potential vanilloid‐1 (TRPV1) is an ion channel involved in several physiological responses, including arterial pressure regulation. This channel seems to have an important role in endothelium‐dependent and ‐independent vasodilation. In spontaneously hypertensive rats (SHRs), chronic treatment with a TRPV1 agonist decreases mean arterial pressure, which makes the TRPV1 a potential target for hypertension treatment. We have already shown that in normotensive rats, the acute blockage of TRPV1 channels leads to an exaggerated increase in mean arterial pressure and heart rate during physical exercise. Therefore, in this study we investigated whether the role of TRPV1 channels in cardiovascular responses during physical exercise is affected by arterial hypertension.MethodsMale Wistar normotensive and Wistar‐Kyoto SHRs (16–19 wk) were implanted with an intra‐arterial (ascending aorta) catheter to measure arterial pressure. The rats received an intra‐arterial injection of a TRPV1 antagonist N‐(4‐[6‐(4‐trifluoromethyl‐phenyl)‐pyrimidin‐4‐yloxy]‐benzothiazol‐2‐yl)‐acetamide (AMG 517, 60 μg/kg) or vehicle (20% ethanol in saline) and then were subjected to an incremental‐speed treadmill running at 24°C until fatigue. The pulsatile arterial pressure (which allowed the determination of mean, systolic and diastolic arterial pressures and the heart rate) was measured throughout the exercise period.ResultsIn both normotensive rats and SHR, the incremental exercise increased mean, systolic and diastolic arterial pressures and the heart rate (for mean arterial pressure, fatigue: Normotensive: 126 ± 3 mmHg; SHR: 165 ± 4 mmHg versus beginning of exercise: Normotensive: 108 ± 4 mmHg; SHR: 158 ± 5 mmHg). As expected, in the normotensive rats, the AMG 517 led to a greater exercise‐induced increases in the mean, systolic and diastolic arterial pressures and in the heart rate. In contrast, the TRPV1 antagonist had no effect on any of the cardiovascular variables evaluated in the SHRs (for mean arterial pressure, min 19: AMG 517: 161 ± 5 mmHg; Vehicle 164 ± 4 mmHg). The changes (values at fatigue minus values at the beginning of exercise) in the mean arterial pressure (Normotensive: 20.1 ± 1.8 mmHg versus SHR 10.5 ± 3.3 mmHg; p &lt; 0.05) as well as in the heart rate (Normotensive: 196 ± 13 bpm versus SHR: 149 ± 9 bpm, p &lt; 0.05) were greater in normotensive rats than in SHRs when the incremental exercise was performed after the TRPV1 antagonist injection.ConclusionsDespite inducing marked alterations in blood pressure regulation in the normotensive rats, the TRPV1 antagonist injection did not modify the cardiovascular responses to exercise in the SHRs, which suggests that the arterial hypertension affects the TRPV1‐mediated mechanism involved in arterial pressure regulation during exercise.Support or Funding InformationCAPES, CNPq and FAPEMIG.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Pharmacological Characterization of Aprocitentan, a Dual Endothelin Receptor Antagonist, Alone and in Combination with Blockers of the Renin Angiotensin System, in Two Models of Experimental Hypertension.

The endothelin (ET) system has emerged as a novel target for hypertension treatment where a medical need persists despite availability of several pharmacological classes, including renin angiotensin system (RAS) blockers. ET receptor antagonism has demonstrated efficacy in preclinical models of hypertension, especially under low-renin conditions and in hypertensive patients. We investigated the pharmacology of aprocitentan (N-[5-(4-bromophenyl)-6-[2-[(5-bromo-2-pyrimidinyl)oxy]ethoxy]-4-pyrimidinyl]-sulfamide), a potent dual ETA/ETB receptor antagonist, on blood pressure (BP) in two models of experimental hypertension: deoxycorticosterone acetate (DOCA)-salt rats (low-renin model) and spontaneously hypertensive rats [(SHR), normal renin model]. We also compared the effect of its combination with RAS blockers (valsartan and enalapril) with that of the combination of the mineraloreceptor antagonist spironolactone with the same RAS blockers on BP and renal function in hypertensive rats. Aprocitentan was more potent and efficacious in lowering BP in conscious DOCA-salt rats than in SHRs. In DOCA-salt rats, single oral doses of aprocitentan induced a dose-dependent and long-lasting BP decrease and 4-week administration of aprocitentan dose dependently decreased BP (statistically significant) and renal vascular resistance, and reduced left ventricle hypertrophy (nonsignificant). Aprocitentan was synergistic with valsartan and enalapril in decreasing BP in DOCA-salt rats and SHRs while spironolactone demonstrated additive effects with these RAS blockers. In hypertensive rats under sodium restriction and enalapril, addition of aprocitentan further decreased BP without causing renal impairment, in contrast to spironolactone. In conclusion, ETA/ETB receptor antagonism represents a promising therapeutic approach to hypertension, especially with low-renin characteristics, and could be used in combination with RAS blockers, without increasing the risk of renal impairment.

Clinical Significance and Therapeutic Implication of Nocturnal Hypertension: Relationship between Nighttime Blood Pressure and Quality of Sleep.

Recent global hypertension guidelines recommend an early, strict and 24-hour blood pressure (BP) control for the prevention of target organ damage and cardiovascular events. Out-of-office BP measurement such as ambulatory BP monitoring and home BP monitoring is now widely utilized to rule out white-coat hypertension, to detect masked hypertension, to evaluate the effects of antihypertensive medication, to analyze diurnal BP variation, and to increase drug adherence. Nocturnal hypertension has been neglected in the management of hypertension despite of its clinical significance. Nighttime BP and non-dipping patterns of BP are stronger risk predictors for the future cardiovascular mortality and morbidity than clinic or daytime BP. In addition to ambulatory or home daytime BP and 24-hour mean BP, nocturnal BP should be a new therapeutic target for the optimal treatment of hypertension to improve prognosis in hypertensive patients. This review will provide an overview of epidemiology, characteristics, and pathophysiology of nocturnal hypertension and clinical significance, therapeutic implication and future perspectives of nocturnal hypertension will be discussed.

Ratiometric fluorescence imaging of Golgi H2O2 reveals a correlation between Golgi oxidative stress and hypertension.

Golgi oxidative stress is significantly associated with the occurrence and progression of hypertension. Notably, the concentration of hydrogen peroxide (H2O2) is directly proportional to the degree of Golgi oxidative stress. Therefore, based on a novel Golgi-targeting phenylsulfonamide group, we developed a two-photon (TP) fluorescent probe, Np-Golgi, for in situ H2O2 ratiometric imaging in living systems. The phenylsulfonamide moiety effectively assists Np-Golgi in the precise location of Golgi apparatus. In addition, the raw material of phenylsulfonamide is easily available, and chemical modification is easily implemented. By application of Np-Golgi, we explored the generation of H2O2 during Golgi oxidative stress, and also successfully revealed increases on the levels of Golgi H2O2 in the kidneys of mice with hypertension. This work provides an ideal tool to monitor Golgi oxidative stress for the first time and novel drug targets for the future treatment of hypertension.

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.

Pomegranate extract decreases oxidative stress and alleviates mitochondrial impairment by activating AMPK-Nrf2 in hypothalamic paraventricular nucleus of spontaneously hypertensive rats.

High blood pressure, or “hypertension,” is associated with high levels of oxidative stress in the paraventricular nucleus of the hypothalamus. While pomegranate extract is a known antioxidant that is thought to have antihypertensive effects, the mechanism whereby pomegranate extract lowers blood pressure and the tissue that mediates its antihypertensive effects are currently unknown. We have used a spontaneously hypertensive rat model to investigate the antihypertensive properties of pomegranate extract. We found that chronic treatment of hypertensive rats with pomegranate extract significantly reduced blood pressure and cardiac hypertrophy. Furthermore, pomegranate extract reduced oxidative stress, increased the antioxidant defense system, and decreased inflammation in the paraventricular nucleus of hypertensive rats. We determined that pomegranate extract reduced mitochondrial superoxide anion levels and increased mitochondrial function in the paraventricular nucleus of hypertensive rats by promoting mitochondrial biogenesis and improving mitochondrial dynamics and clearance. We went on to identify the AMPK-nuclear factor-erythroid 2 p45-related factor 2 (Nrf2) pathway as a mechanism whereby pomegranate extract reduces oxidative stress in the paraventricular nucleus to relieve hypertension. Our findings demonstrate that pomegranate extract alleviates hypertension by reducing oxidative stress and improving mitochondrial function in the paraventricular nucleus, and reveal multiple novel targets for therapeutic treatment of hypertension.

Evidence to Maintain the Systolic Blood Pressure Treatment Threshold at 140 mm Hg for Stroke Prevention: The Northern Manhattan Study.

In 2014, the Eighth Joint National Committee revised the target maximum systolic blood pressure (SBP) from 140 to 150 mm Hg in patients aged ≥60 years without diabetes mellitus or chronic kidney disease. The evidence from cohort studies supporting this change was sparse, particularly among US minority populations. In the Northern Manhattan Study, 1750 participants aged ≥60 years and free of stroke, diabetes mellitus, and chronic kidney disease had SBP measured at baseline and were annually followed up for incident stroke. Mean age at baseline was 72±8 years, 63% were women, 48% Hispanic, 25% non-Hispanic white, and 25% non-Hispanic black. Among all participants, 40% were on antihypertensive medications; 43% had SBP <140 mm Hg, 20% had 140 to 149 mm Hg, and 37% had ≥150 mm Hg. Over a median follow-up of 13 years, 182 participants developed stroke. The crude stroke incidence was greater among individuals with SBP≥150 mm Hg (10.8 per 1000 person-years) and SBP 140 to 149 (12.3) than among those with SBP<140 (6.2). After adjusting for demographics, vascular risk factors, diastolic BP, and medication use, participants with SBP 140 to 149 mm Hg had an increased risk of stroke (hazard ratio, 1.7; 95% confidence interval, 1.2-2.6) compared with those with SBP <140 mm Hg. The increased stroke risk was most notable among Hispanics and non-Hispanic blacks. Raising the SBP threshold from 140 to 150 mm Hg as a new target for hypertension treatment in older individuals without diabetes mellitus or chronic kidney disease could have a detrimental effect on stroke risk reduction, especially among minority US populations.