Human Hypertension Research Articles

Biallelic NPR1 loss of function variants are responsible for neonatal systemic hypertension

BackgroundEarly-onset isolated systemic hypertension is a rare condition of unknown genetic origin. Renovascular, renal parenchymal diseases or aortic coarctation are the most common causes of secondary systemic hypertension in younger...

Central and peripheral chemoreflexes in humans with treated hypertension.

Increased peripheral chemoreflex sensitivity is a pathogenic feature of human hypertension (HTN), while both central and peripheral chemoreflex sensitivities are reportedly augmented in animal models of HTN. Herein, we tested the hypothesis that both central and combined central and peripheral chemoreflex sensitivities are augmented in HTN. Fifteen HTN participants (68±5years; mean±SD) and 13 normotensives (NT; 65±6years) performed two modified rebreathing protocols in which the partial pressure of end-tidal carbon dioxide ( ) progressively increased while the partial pressure of end-tidal oxygen was clamped at either 150mmHg (isoxic hyperoxia; central chemoreflex activation) or 50mmHg (isoxic hypoxia; combined central and peripheral chemoreflex activation). Ventilation ( ; pneumotachometer) and muscle sympathetic nerve activity (MSNA; microneurography) were recorded, and ventilatory ( vs. slope) and sympathetic (MSNA vs. slope) chemoreflex sensitivities and recruitment thresholds (breakpoint) were calculated. Global cerebral blood flow (gCBF; duplex Doppler) was measured, and the association with chemoreflex responses was examined. Central ventilatory and sympathetic chemoreflex sensitivities were greater in HTN than NT (2.48±1.33 vs. 1.58±0.42Lmin-1 mmHg-1 , P=0.030: 3.32±1.90 vs. 1.77±0.62a.u.mmHg-1 , P=0.034, respectively), while recruitment thresholds were not different between groups. HTN and NT had similar combined central and peripheral ventilatory and sympathetic chemoreflex sensitivities and recruitment thresholds. A lower gCBF was associated with an earlier recruitment threshold for (R2 =0.666, P<0.0001) and MSNA (R2 =0.698, P=0.004) during isoxic hyperoxic rebreathing. These findings indicate that central ventilatory and sympathetic chemoreflex sensitivities are augmented in human HTN and perhaps suggest that targeting the central chemoreflex may help some forms of HTN. KEY POINTS: In human hypertension (HTN) increased peripheral chemoreflex sensitivity has been identified as a pathogenic feature, and in animal models of HTN, both central and peripheral chemoreflex sensitivities are reportedly augmented. In this study, the hypothesis was tested that both central and combined central and peripheral chemoreflex sensitivities are augmented in human HTN. We observed that both central ventilatory and sympathetic chemoreflex sensitivities were augmented in HTN compared to age-matched normotensive controls, but no difference was found in the combined central and peripheral ventilatory and sympathetic chemoreflex sensitivities. During central chemoreflex activation, the ventilatory and sympathetic recruitment thresholds were lower in those with lower total cerebral blood flow. These results indicate a potential contributory role of the central chemoreceptors in the pathogenesis of human HTN and support the possibility that therapeutic targeting of the central chemoreflex may help some forms of HTN.

Dopamine Receptor D1R and D3R and GRK4 Interaction in Hypertension.

Essential hypertension is caused by the interaction of genetic, behavioral, and environmental factors. Abnormalities in the regulation of renal ion transport cause essential hypertension. The renal dopaminergic system, which inhibits sodium transport in all the nephron segments, is responsible for at least 50% of renal sodium excretion under conditions of moderate sodium excess. Dopaminergic signals are transduced by two families of receptors that belong to the G protein-coupled receptor (GPCR) superfamily. D1-like receptors (D1R and D5R) stimulate, while D2-like receptors (D2R, D3R, and D4R) inhibit adenylyl cyclases. The dopamine receptor subtypes, themselves, or by their interactions, regulate renal sodium transport and blood pressure. We review the role of the D1R and D3R and their interaction in the natriuresis associated with volume expansion. The D1R- and D3R-mediated inhibition of renal sodium transport involves PKA and PKC-dependent and -independent mechanisms. The D3R also increases the degradation of NHE3 via USP-mediated ubiquitinylation. Although deletion of Drd1 and Drd3 in mice causes hypertension, DRD1 polymorphisms are not always associated with human essential hypertension and polymorphisms in DRD3 are not associated with human essential hypertension. The impaired D1R and D3R function in hypertension is related to their hyper-phosphorylation; GRK4γ isoforms, R65L, A142V, and A486V, hyper-phosphorylate and desensitize D1R and D3R. The GRK4 locus is linked to and GRK4 variants are associated with high blood pressure in humans. Thus, GRK4, by itself, and by regulating genes related to the control of blood pressure may explain the "apparent" polygenic nature of essential hypertension.

The Effect of Hypoxia-inducible Factor Inhibition on the Phenotype of Fibroblasts in Human and Bovine Pulmonary Hypertension.

Hypoxia-inducible factor (HIF) has received much attention as a potential pulmonary hypertension (PH) treatment target because inhibition of HIF reduces the severity of established PH in rodent models. However, the limitations of small-animal models of PH in predicting the therapeutic effects of pharmacologic interventions in humans PH are well known. Therefore, we sought to interrogate the role of HIFs in driving the activated phenotype of PH cells from human and bovine vessels. We first established that pulmonary arteries (PAs) from human and bovine PH lungs exhibit markedly increased expression of direct HIF target genes (CA9, GLUT1, and NDRG1), as well as cytokines/chemokines (CCL2, CSF2, CXCL12, and IL6), growth factors (FGF1, FGF2, PDGFb, and TGFA), and apoptosis-resistance genes (BCL2, BCL2L1, and BIRC5). The expression of the genes found in the intact PAs was determined in endothelial cells, smooth muscle cells, and fibroblasts cultured from the PAs. The data showed that human and bovine pulmonary vascular fibroblasts from patients or animals with PH (termed PH-Fibs) were the cell type that exhibited the highest level and the most significant increases in the expression of cytokines/chemokines and growth factors. In addition, we found that human, but not bovine, PH-Fibs exhibit consistent misregulation of HIFα protein stability, reduced HIF1α protein hydroxylation, and increased expression of HIF target genes even in cells grown under normoxic conditions. However, whereas HIF inhibition reduced the expression of direct HIF target genes, it had no impact on other "persistently activated" genes. Thus, our study indicated that HIF inhibition alone is not sufficient to reverse the persistently activated phenotype of human and bovine PH-Fibs.

Novel Loss of Function KCNA5 Variants in Pulmonary Arterial Hypertension.

Reduced expression and/or activity of Kv1.5 channels (encoded by KCNA5) is a common hallmark in human or experimental pulmonary arterial hypertension (PAH). Likewise, genetic variants in KCNA5 have been found in PAH patients, but their functional consequences and potential impact on the disease are largely unknown. Herein, we aimed to characterize the functional consequences of 7 KCNA5 variants found in a cohort of PAH patients. Potassium currents were recorded by patch-clamp technique in HEK293 cells transfected with WT or mutant Kv1.5 cDNA. Flow cytometry, western blot and confocal microscopy techniques were used for measuring protein expression and cell apoptosis in HEK293 and human pulmonary artery smooth muscle cells (hPASMC). KCNA5 variants found in PAH patients (namely, p.Arg184Pro and p.Gly384Arg) resulted in a clear loss of potassium channel function as assessed by electrophysiological and molecular modelling analyses. The p.Arg184Pro variant also resulted in a pronounced reduction of Kv1.5 expression. Transfection with p.Arg184Pro or p.Gly384Arg variants decreased apoptosis of hPASMCs compared with the WT, demonstrating that KCNA5 dysfunction in both variants affects cell viability. Thus, in addition to affecting channel activity, both variants were associated with impaired apoptosis, a crucial process linked to the disease. The estimated prevalence of dysfunctional KCNA5 variants in the PAH population analyzed was around 1 %. Our data indicate that some KCNA5 variants found PAH patients have critical consequences for channel function supporting the idea that KCNA5 pathogenic variants may be a causative or contributing factor for PAH.

Urine Cell Transcriptomes Implicate Specific Renal Inflammatory Pathways Associated With Difficult-to-Control Hypertension.

Background The renal mechanisms involved in the maintenance of human hypertension and resistance to treatment are not well understood. Animal studies suggest that chronic renal inflammation contributes to hypertension. We studied cells shed in first-morning urine samples from individuals who were hypertensive who exhibited difficult-to-control blood pressure (BP). We performed bulk RNA sequencing of these shed cells to develop transcriptome-wide associations with BP. We also analyzed nephron-specific genes and used an unbiased bioinformatic approach to find signaling pathways activated in difficult-to-control hypertension. Methods and Results Participants who completed the SPRINT (Systolic Blood Pressure Intervention Trial) at a single trial site were recruited, and cells shed in first-morning urine samples collected. A total of 47 participants were divided into 2 groups based on hypertension control. The BP-difficult group (n=29) had systolic BP>140 mm Hg, >120 mm Hg after intensive treatment for hypertension, or required more than the median number of antihypertensive drugs used in SPRINT. The easy-to-control BP group (n=18) comprised the remainder of the participants. A total of 60 differentially expressed genes were identified with a >2-fold change in the BP-difficult group. In BP-difficult participants, 2 of the most upregulated genes were associated with inflammation: Tumor Necrosis Factor Alpha Induced Protien 6 (fold change, 7.76; P=0.006) and Serpin Family B Member 9 (fold change, 5.10; P=0.007). Biological pathway analysis revealed an overrepresentation of inflammatory networks, including interferon signaling, granulocyte adhesion and diapedesis, and Janus Kinase family kinases in the BP-difficult group (P<0.001). Conclusions We conclude that transcriptomes from cells shed in first-morning urine identify a gene expression profile in difficult-to-control hypertension that associates with renal inflammation.

Roles of Hydrogen Sulfide in Hypertension Development and Its Complications: What, So What, Now What.

Hypertension is a multicause health challenge, and hydrogen sulfide (H2S) is a multifunctional gasotransmitter. A critical pathologic role of endogenous H2S deficiency in the development of hypertension was established 15 years ago based on animal studies, setting the stage for examining the wide spectrum of cardiovascular effects and the underlying molecular and cellular mechanisms of H2S. We are also starting to gain a better understanding of the role of altered H2S metabolism in human hypertension. The purpose of this article is to examine our current understanding of the roles played by H2S in the development of hypertension in both animals and humans. Additionally, H2S-based antihypertension therapeutic strategies are reviewed. Is H2S at the root of hypertension and one of the solutions for the same? The probability is very high.

Natriuretic Peptides: It Is Time for Guided Therapeutic Strategies Based on Their Molecular Mechanisms.

Natriuretic peptides (NPs) are the principal expression products of the endocrine function of the heart. They exert several beneficial effects, mostly mediated through guanylate cyclase-A coupled receptors, including natriuresis, diuresis, vasorelaxation, blood volume and blood pressure reduction, and regulation of electrolyte homeostasis. As a result of their biological functions, NPs counterbalance neurohormonal dysregulation in heart failure and other cardiovascular diseases. NPs have been also validated as diagnostic and prognostic biomarkers in cardiovascular diseases such as atrial fibrillation, coronary artery disease, and valvular heart disease, as well as in the presence of left ventricular hypertrophy and severe cardiac remodeling. Serial measurements of their levels may be used to contribute to more accurate risk stratification by identifying patients who are more likely to experience death from cardiovascular causes, heart failure, and cardiac hospitalizations and to guide tailored pharmacological and non-pharmacological strategies with the aim to improve clinical outcomes. On these premises, multiple therapeutic strategies based on the biological properties of NPs have been attempted to develop new targeted cardiovascular therapies. Apart from the introduction of the class of angiotensin receptor/neprilysin inhibitors to the current management of heart failure, novel promising molecules including M-atrial natriuretic peptide (a novel atrial NP-based compound) have been tested for the treatment of human hypertension with promising results. Moreover, different therapeutic strategies based on the molecular mechanisms involved in NP regulation and function are under development for the management of heart failure, hypertension, and other cardiovascular conditions.

Óxido nítrico plasmático em cães com hipertensão pulmonar secundária ou não à doença cardíaca esquerda

ABSTRACT Nitric oxide (NO) is an important mediator responsible for vasodilation in pulmonary hypertension (PH) in humans. Based on human literature, it is suggested that in dogs there is also NO production decrease in lung tissue in the presence of PH with hypoxia. Therefore, the aim of this research was to determine the indirect plasmatic NO concentration in dogs with PH secondary or not to the left-side heart disease (LHD) and also with low, intermediate and high probability of PH to characterize the NO involvement on PH in dogs. Blood samples were collected from 35 dogs with probability of PH to NO measurement. NO concentration was estimated by the nitrite/nitrate concentration, and it was significantly different (p=0.002) in dogs with PH secondary to LHD (median=14 µM, range 11.19-16.59) and not secondary to LHD (median=25.88µM, range 15.08-36.71). However, this was not significant for the probability of low, intermediate, and high PH, although there was a tendency for NO concentration to be higher in dogs with high PH. The results of this study demonstrate that there is release of NO in dogs with PH, as well as that its dosage could differentiate dogs with PH secondary to LHD from dogs with non-secondary PH.

Sotatercept analog improves cardiopulmonary remodeling and pulmonary hypertension in experimental left heart failure.

Pulmonary hypertension due to left heart disease (PH-LHD) is the most frequent manifestation of PH but lacks any approved treatment. Activin receptor type IIA-Fc fusion protein (ActRIIA-Fc) was found previously to be efficacious in experimental and human pulmonary arterial hypertension (PAH). Here we tested the hypothesis that ActRIIA-Fc improves pulmonary vascular remodeling and alleviates PH in models of PH-LHD, specifically in subtypes of heart failure with reduced ejection fraction (PH-HFrEF) and preserved ejection fraction (PH-HFpEF). Treatment with murine ActRIIA-Fc reduced cardiac remodeling and improved cardiac function in two mouse models of left heart disease without PH, confirming that this inhibitor of activin-class ligand signaling can exert cardioprotective effects in heart failure. In a mouse model of PH-HFrEF with prolonged pressure overload caused by transverse aortic constriction, ActRIIA-Fc treatment significantly reduced pulmonary vascular remodeling, pulmonary fibrosis, and pulmonary hypertension while exerting beneficial structural, functional, and histological effects on both the left and right heart. Additionally, in an obese ZSF1-SU5416 rat model of PH-HFpEF with metabolic dysregulation, therapeutic treatment with ActRIIA-Fc normalized SMAD3 overactivation in pulmonary vascular and perivascular cells, reversed pathologic pulmonary vascular and cardiac remodeling, improved pulmonary and cardiac fibrosis, alleviated PH, and produced marked functional improvements in both cardiac ventricles. Studies in vitro revealed that treatment with ActRIIA-Fc prevents an abnormal, glucose-induced, activin-mediated, migratory phenotype in human pulmonary artery smooth muscle cells, providing a mechanism by which ActRIIA-Fc could exert therapeutic effects in experimental PH-HFpEF with metabolic dysregulation. Our results demonstrate that ActRIIA-Fc broadly corrects cardiopulmonary structure and function in experimental PH-LHD, including models of PH-HFrEF and PH-HFpEF, leading to alleviation of PH under diverse pathophysiological conditions. These findings highlight the important pathogenic contributions of activin-class ligands in multiple forms of experimental PH and support ongoing clinical evaluation of human ActRIIA-Fc (sotatercept) in patients with PH-HFpEF.

The Association between Genetic Variants and Gene Expression in RAAS Genes Using Captive-Bred Vervet Monkeys (Chlorocebus aethiops)

Mendelian genetics contribute largely to the development of hypertension; therefore, the identification of genetic variants related to blood pressure (BP) regulation remains crucial and may reveal new therapeutic drug targets. The purpose of the present study was to screen the captive-bred Vervet colony for salt-sensitive sequence variants or single nucleotide polymorphisms (SNPs) in the selected Renin-Angiotensin-Aldosterone System (RAAS) genes associated with salt sensitivity. Blood samples were collected from 16 captive-bred Vervet monkeys for genotyping and gene expression analysis. The impact of the identified sequence variants was determined using online prediction tools. Sanger sequencing analysis revealed 21 sequence variants in AGT, CYP3A5, GRK4, and SCL4A5, of which 19 were novel and two were previously reported in humans. All novel variants were either predicted to be polymorphic, disease-causing, or possibly damaging by prediction tools. Furthermore, the mRNA expression for AGT was significantly higher in the normal BP group ( p value = 0.02), and a similar trend was observed for CYP3A5 and GRK4, whereas SCL4A5 was higher in the hypertensive group. The identified salt-sensitive variants specifically in GRK4 may be suggestive to be the attributing factor of the elevated BP levels in these captive-bred Vervet monkeys. Therefore, RAAS variants could be considered as a biomarker to identify the potential risk of developing hypertension in both humans and nonhuman primates.

Human Omentin-1 Administration Ameliorates Hypertensive Complications without Affecting Hypertension in Spontaneously Hypertensive Rats.

Hypertension is one of the major risk factors for cardiovascular diseases and is caused by various abnormalities including the contractility of blood vessels. Spontaneously hypertensive rats (SHR), whose systemic blood pressure increases with aging, are a frequently used animal model for investigating essential hypertension and related complications in humans due to the damage of several organs. Human omentin-1 is an adipocytokine consisting of 313 amino acids. Serum omentin-1 levels decreased in hypertensive patients compared with normotensive controls. Furthermore, omentin-1 knockout mice showed elevated blood pressure and impaired endothelial vasodilation. Taken together, we hypothesized that adipocytokine, human omentin-1 may improve the hypertension and its complications including heart and renal failure in the aged SHR (65-68-weeks-old). SHR were subcutaneously administered with human omentin-1 (18 μg/kg/day, 2 weeks). Human omentin-1 had no effect on body weight, heart rate, and systolic blood pressure in SHR. The measurement of isometric contraction revealed that human omentin-1 had no influence on the enhanced vasocontractile or impaired vasodilator responses in the isolated thoracic aorta from SHR. On the other hand, human omentin-1 tended to improve left ventricular diastolic failure and renal failure in SHR. In summary, human omentin-1 tended to improve hypertensive complications (heart and renal failure), while it had no influence on the severe hypertension in the aged SHR. The further study of human omentin-1 may lead to the development of therapeutic agents for hypertensive complications.

Altered Neuronal Discharge in the Organum Vasculosum of the Lamina Terminalis Contributes to Dahl Salt-Sensitive Hypertension.

Salt-sensitive hypertension in humans and experimental models is associated with higher plasma and cerebrospinal fluid sodium chloride (NaCl) concentrations. Changes in extracellular NaCl concentrations are sensed by specialized neurons in the organum vasculosum of the lamina terminalis (OVLT). Stimulation of OVLT neurons increases sympathetic nerve activity (SNA) and arterial blood pressure (ABP), whereas chronic activation produces hypertension. Therefore, the present study tested whether OVLT neuronal activity was elevated and contributed to SNA and ABP in salt-sensitive hypertension. Male Dahl salt-sensitive (Dahl S) and Dahl salt-resistant (Dahl R) rats were fed 0.1% or 4.0% NaCl diets for 3 to 4 weeks and used for single-unit recordings of OVLT neurons or simultaneous recording of multiple sympathetic nerves during pharmacological inhibition of the OVLT. Plasma and cerebrospinal fluid Na+ and Cl- concentrations were higher in Dahl S rats fed 4% versus 0.1% or Dahl R rats fed either diet. In vivo single-unit recordings revealed a significantly higher discharge of NaCl-responsive OVLT neurons in Dahl S rats fed 4% versus 0.1% or Dahl R rats. Interestingly, intracarotid infusion of hypertonic NaCl evoked greater increases in OVLT neuronal discharge of Dahl S versus Dahl R rats regardless of NaCl diet. The activity of non-NaCl-responsive OVLT neurons was not different across strain or diets. Finally, inhibition of OVLT neurons by local injection of the gamma-aminobutyric acid agonist muscimol produced a greater decrease in renal SNA, splanchnic SNA, and ABP of Dahl S rats fed 4% versus 0.1% or Dahl R rats. A high salt diet activates NaCl-responsive OVLT neurons to increase SNA and ABP in salt-sensitive hypertension.

High-salt diet augments systolic blood pressure and induces arterial dysfunction in outbred, genetically diverse mice.

Excess salt consumption contributes to hypertension and arterial dysfunction in humans living in industrialized societies. However, this arterial phenotype is not typically observed in inbred, genetically identical mouse strains that consume a high-salt (HS) diet. Therefore, we sought to determine the effects of HS diet consumption on systolic blood pressure (BP) and arterial function in UM-HET3 mice, an outbred, genetically diverse strain of mice. Male and female UM-HET3 mice underwent a low-salt [LS (1% NaCl)] or HS (4% NaCl) diet for 12 wk. Systolic BP and aortic stiffness, determined by pulse wave velocity (PWV), were increased in HS after 2 and 4 wk, respectively, compared with baseline and continued to increase through week 12 (P < 0.05). Systolic BP was higher from weeks 2-12 and PWV was higher from weeks 4-12 in HS compared with LS mice (P < 0.05). Aortic collagen content was ∼81% higher in HS compared with LS (P < 0.05), whereas aortic elastin content was similar between groups (P > 0.05). Carotid artery endothelium-dependent dilation (EDD) was ∼10% lower in HS compared with LS (P < 0.05), endothelium-independent dilation was similar between groups (P > 0.05). Finally, there was a strong relationship between systolic BP and PWV (r2 = 0.40, P < 0.05), as well as inverse relationship between EDD and systolic BP (r2 = 0.21, P < 0.05) or PWV (r2 = 0.20, P < 0.05). In summary, HS diet consumption in UM-HET3 mice increases systolic BP, which is accompanied by aortic stiffening and impaired EDD. These data suggest that outbred, genetically diverse mice may provide unique translational insight into arterial adaptations of humans that consume an HS diet.NEW & NOTEWORTHY Excess salt consumption is a contributor to hypertension and arterial dysfunction in humans living in industrialized societies, but this phenotype is not observed in inbred, genetically identical mice that consume a high-salt (HS) diet. This study reveals that a HS diet in outbred, genetically diverse mice progressively increases systolic blood pressure and induce arterial dysfunction. These data suggest that genetically diverse mice may provide translational insight into arterial adaptations in humans that consume an HS diet.

The association between carbon and nitrogen stable isotope ratios of human hair and hypertension

BackgroundThe relationship between stable isotope ratios and dietary protein sources has been reported. However, few studies have examined the effect of stable isotope ratios on metabolic risk in humans. We investigated whether the stable isotope ratios of carbon and nitrogen in human hair are associated with blood pressure and hypertension.MethodsWe conducted a cross-sectional study of 392 subjects (228 men and 164 women). Hair samples of the subjects were used for the measurement of stable isotope ratios of carbon (δ13C) and nitrogen (δ15N).ResultsThe δ13C and δ15N values showed positive correlations with diastolic blood pressure in the subjects without antihypertensive medication. In the subjects without antihypertensive medication, the multivariable-adjusted odds ratio (95% confidence interval) for hypertension was 1.55 (1.04–2.30) per 1‰ increase in δ15N and 1.22 (0.86–1.73) per 1‰ increase in δ13C, respectively. However, in the subjects with antihypertensive medication, neither δ13C nor δ15N values showed a significant association with hypertension.ConclusionsThe stable isotopic ratio of nitrogen in scalp hair is independently associated with hypertension in subjects without antihypertensive medication. The hair δ15N value might be used as a surrogate marker to screen a high-risk population for hypertension.

Disease burden among migrants in Morocco in 2021: A cross‑sectional study.

Morocco, traditionally an emigration country, has evolved into not only a transit country to Europe but also a country of residence for an increasing number of migrants, with 102,400 migrants in 2019. This is due to its geographic location, the induced effects of its "African policy," and the various laws adopted by Moroccan legislators in recent years. The purpose of this study is to determine the prevalence of communicable and noncommunicable diseases among migrants such as Hepatitis C virus (HCV), human immunodeficiency virus (HIV), diabetes, and hypertension. We conducted a cross-sectional study in Oujda, Morocco, between November and December 2021. Face-to-face interviews with enrolled migrants aged 18 years and over, present in Oujda and attending an association, were carried out to collect socio-demographic data, lifestyle behaviors, and clinical parameters. Diabetes and hypertension were the primary outcomes. The Pearson's chi-squared test and the student's t-test were used to assess the bivariate associations between primary outcomes and categorical and continuous variables. In a multivariate model, we adjusted for predictors that were significant (p-value ≤0.05) in bivariate analysis to estimate Adjusted Odd Ratios (AOR) and 95% confidence intervals (CI). There were 495 migrants enrolled, with a male/female ratio of two and an average age of 27.3±11.5 years (mean±standard deviation), ranging from 18 to 76 years. Hepatitis C virus, human immunodeficiency virus, diabetes, and hypertension were found in 1%, 0.2%, 3.8%, and 27.7% of the population, respectively. Family history of diabetes was a risk factor for diabetes in the Oujda migrant population, with an Adjusted Odds Ratio (AOR) of 5.36; CI% [1.23-23.28]. Age (AOR of 1.1; CI% [1.06-1.13]) and African origin (AOR of 3.07; CI% [1.06-8.92]) were identified as risk factors for hypertension. Migrants in Oujda are healthy. The high prevalence of hypertension, as well as the presence of HCV and HIV positive cases, emphasizes the importance of routine screening for hypertension, HCV, and HIV in order to detect and treat these diseases as early as possible.

The mechanism of low-level arsenic exposure-induced hypertension: Inhibition of the activity of the angiotensin-converting enzyme 2

It is now well-established that arsenic exposure induces hypertension in humans. Although arsenic-induced hypertension is reported in many epidemiological studies, the underlying molecular mechanism of arsenic-induced hypertension is not fully characterized. In the human body, blood pressure is primarily regulated by a well-known physiological system known as the renin-angiotensin system (RAS). Hence, we explored the potential molecular mechanisms of arsenic-induced hypertension by investigating the regulatory roles of the RAS. Adult C57BL/6JJcl male mice were divided into four groups according to the concentration of arsenic in drinking water (0, 8, 80, and 800 ppb) provided for 8 weeks. Arsenic significantly raised blood pressure in arsenic-exposed mice compared to the control group, and significantly raised plasma MDA and Ang II and reduced Ang (1–7) levels. RT-PCR results showed that arsenic significantly downregulated ACE2 and MasR in mice aortas. In vitro studies of endothelial HUVEC cells treated with arsenic showed increased level of MDA and Ang II and lower levels of Ang (1–7), compared with the control. Arsenic significantly downregulated ACE2 and MasR expression, as well as those of Sp1 and SIRT1; transcriptional activators of ACE2, in HUVECs. Arsenic also upregulated markers of endothelial dysfunction (MCP-1, ICAM-1) and inflammatory cytokines (IL-6, TNF-α) in HUVECs. Our findings suggest that arsenic-induced hypertension is mediated, at least in part, by oxidative stress-mediated inhibition of ACE2 as well as by suppressing the vasoprotective axes of RAS, in addition to the activation of the classical axis.

Long-Term Impact of the Great Chinese Famine on the Risks of Specific Arrhythmias and Severe Hypertension in the Offspring at an Early Stage of Aging.

Perinatal malnutrition affects postnatal cardiovascular functions. This study used the Great Chinese Famine (GCF) to determine the long-term impact of perinatal undernutrition on hypertension and arrhythmias in older offspring. Subjects (n = 10,065) were divided into an exposed group whose fetal life was in the GCF and an unexposed group. The exposed group showed higher systolic/diastolic pressure, heart rate, and total cholesterol. Perinatal exposure to the GCF was a significant risk to Grade 2 and Grade 3 hypertension (OR = 1.724, 95%CI: 1.441-2.064, p < 0.001; OR = 1.480, 95%CI: 1.050-2.086, p < 0.05) compared to the control. The GCF also increased risks for myocardial ischemia (OR = 1.301, 95%CI: 1.135-1.490, p < 0.001), bradycardia (OR = 1.383, 95%CI: 1.154-1.657, p < 0.001), atrial fibrillation (OR = 1.931, 95%CI: 1.033-3.610, p < 0.05), and atrioventricular block (OR = 1.333, 95%CI: 1.034-1.719, p < 0.05). Total cholesterol, diabetes, and metabolic syndrome were associated with Grade 2 or Grade 3 hypertension after exposure to the GCF; high cholesterol, high BMI, diabetes, metabolic syndrome, and elevated blood pressure were linked to certain types of arrhythmias in exposed offspring. The results first demonstrated perinatal undernutrition was a significant risk factor for the development of Grade 2-3 hypertension and certain arrhythmias in humans. Perinatal undernutrition still significantly impacted cardiovascular systems of the aged offspring even 50 years after the GCF. The results also provided information to a specific population with a history of prenatal undernutrition for early prevention against cardiovascular diseases before aging.

Immune Profiling Reveals Decreases in Circulating Regulatory and Exhausted T Cells in Human Hypertension

Evidence from nonhuman animal models demonstrates an important role for immune cells in hypertension, butimmune cell changes in human hypertension are less clear. Using mass cytometry, we demonstrate novel and selective reductions in CCR10+ regulatory T cells (Tregs) and PD-1+CD57-CD8+ memory T cells. RNA sequencing reveals that CCR10+ Tregs exhibit gene expression changes consistent with enhanced immunosuppressive function. In addition, CITE-Seq demonstrates that PD-1+CD57-CD8+ memory T cells exhibit features of T-cell exhaustion. Taken together, these results provide novel evidence for decreases in anti-inflammatory and/or hypofunctional T-cell populations that may contribute to enhanced inflammation inhuman hypertension.

S-07-4: VASCULAR SMOOTH MUSCLE CELL PROTEOME AND PHENOTYPIC SWITCHING IN HUMAN HYPERTENSION ARE NOX5-DEPENDENT

Objective: Reactive oxygen species (ROS) play a key role in the regulation of vascular smooth muscle cell (VSMC) phenotypic switching in hypertension. Nox5 is a major ROS-generating enzyme in vascular cells and is upregulated in hypertension. However, the effects of Nox5-derived ROS on VSMC proteome and phenotype in human hypertension are unknown. We aimed to characterize the global and oxidative proteomic profile and VSMC phenotype in human hypertension and the role of Nox5. Design and method: VSMC from resistance arteries from normotensive (NT) and hypertensive (HT) subjects were studied (n = 5). Proteins were labelled with isobaric tandem mass tags and identified by liquid chromatography tandem mass spectrometry. The oxidative proteome was assessed using stable isotope-labelled iodoacetamide to target cysteine thiols. Nox5 silencing was performed by siRNA. Protein expression was detected by western blotting. The inflammatory, pro-fibrotic and mitogenic phenotype of VSMCs was assessed by measuring pro-inflammatory cytokines (IL-6, IL-8), pro-collagen I in the culture media. Results: Proteomic analysis identified 207 proteins upregulated in HT subjects (fold change &gt; 1.5, p &lt; 0.05). Gene ontology enrichment analysis of upregulated proteins in HT showed most proteins belong to extracellular space and plasma membrane compartments and were involved in extracellular matrix organization (ECM), immune response and cell proliferation. ECM proteins COL1A1, COL9A1, COL10A1, FBN1, FBLN1 were increased in cells from HT, suggesting a switch to a fibroblast-like phenotype in hypertension. Expression of proteins related to interferon and IL-1β pathways (IFIT1, IFIT2, IFIT3, MX1, MX2, ABCA1, ABCA2, IL1RAP, CD36, ICAM1) were also increased in cells from HT subjects. The VSMC oxidative proteome analysis identified 130 significantly regulated cysteine-containing peptides, 88 showed increased oxidation in HT (fold change&gt; 1.5, p &lt; 0.05). Among the highly oxidized proteins in HT were ECM proteins, COL11A1, COL16A1, FBLN1 and FBLN2. VSMCs from HT subjects exhibit increased expression of the proliferation marker, PCNA (0.162 ± 0.3 vs NT:0.051 ± 0.04 relative fluorescence units, p &lt; 0.05) and pro-collagen I (23.6 ± 2 vs NT:13.2 ± 0.3 ng/ml, p &lt; 0.05). Production of pro-inflammatory cytokines IL-6 (501.8 ± 23.6 vs NT:121.7 ± 6.4 pg/mL) and IL-8 (373.6 ± 34.1 vs NT:262.5 ± 24.6 pg/mL, p &lt; 0.05) were increased in HT. Nox5 silencing in VSMC from HT subjects reduced PCNA expression(43%), pro-collagen I release (8%), baseline and LPS-induced IL-6 (30% baseline, 43% LPS-induced) and IL-8 (21% baseline, 23% LPS-induced) release (p &lt; 0.05). Conclusions: Our study provides new insights into the proteomic changes related to vascular phenotype in hypertension and demonstrated that Nox5 plays an important role in VSMC phenotypic switching associated with vascular injury and remodelling in hypertension.