Genesis Of Hypertension Research Articles

Lipid droplets in the endothelium: The missing link between metabolic syndrome and cardiovascular disease?

The physiology of lipid droplets (LDs) has been most extensively characterized in adipocytes, but LDs also accumulate in endothelial cells lining blood vessels in response to changing levels of triglycerides. In recent issues of the JCI, two independent papers highlight a direct role of endothelial LDs in the genesis of hypertension and atherosclerosis in rodent models. Kim et al. demonstrated that accumulation of LDs in the endothelium leads to hypertension, impairs endothelial function, and accelerates atherosclerosis. Boutagy, Gamez-Mendez, et al. knocked out Atgl in the endothelium and confirmed triglyceride accumulation in endothelial cells that was associated with reduced NO synthesis and impaired endothelial-dependent vasodilation. These data suggest that enhancing triglyceride breakdown in the endothelium could provide a treatment target for patients with metabolic syndrome.

Calcium Imaging and Amperometric Recording in Cultured Chromaffin Cells and Adrenal Slices from Normotensive, Wistar Kyoto Rats and Spontaneously Hypertensive Rats.

The spontaneously hypertensive rat (SHR) is a model widely used to investigate the causal mechanisms of essential hypertension. The enhanced catecholamine (CA) release reported in adrenal glands from adult SHRs raised considerable interest for its possible implication in the genesis of hypertension. The use of powerful techniques such as calcium imaging, electrophysiology, and single-cell amperometry to monitor in real time the key steps in CA secretion has allowed a better understanding of the role of chromaffin cells (CC) in the pathophysiology of hypertension, although several questions remain. Additionally, the implementation of these techniques in preparations in situ, such as the acute adrenal gland slice, which maintains the microenvironment, cell-to-cell communication, and anatomical structure similar to that of the intact adrenal gland, yields data that may have even greater physiological relevance. Here, we describe the procedures to measure the blood pressure of rats in a noninvasive manner, how to obtain primary cultures of adrenal chromaffin cells and acute adrenal slices, and how to perform amperometric recordings and intracellular calcium imaging in these preparations.

The Bidirectional Signal Communication of Microbiota-Gut-Brain Axis in Hypertension.

Hypertension is a critical risk factor of cardiovascular diseases. A new concept of microbiota-gut-brain axis has been established recently, mediating the bidirectional communication between the gut and its microbiome and the brain. Alterations in bidirectional interactions are believed to be involved in the blood pressure regulation. Neuroinflammation and increased sympathetic outflow act as the descending innervation signals from the brain. Increased sympathetic activation plays a recognized role in the genesis of hypertension. The present evidence demonstrates that gut dysbiosis is associated with central nervous system neuroinflammation. However, how the gut influences the brain remains unclear. We reviewed the roles of neuroinflammation and gut microbiota and their interactions in the pathogenesis of hypertension and described the ascending signaling mechanisms behind the microbiota-gut-brain axis in detail. Additionally, the innovative prohypertensive mechanisms of dietary salt through the microbiota-gut-brain axis are summarized. The bidirectional communication mechanisms were proposed for the first time that the descending signals from the brain and the ascending connections from the gut form a vicious circle of hypertension progression, acting as a premise for hypertension therapy.

Innate immunity and clinical hypertension.

Emerging evidence has supported a role of inflammation and immunity in the genesis of hypertension. In humans and experimental models of hypertension, cells of the innate and adaptive immune system enter target tissues, including vessels and the kidney, and release powerful mediators including cytokines, matrix metalloproteinases and reactive oxygen species that cause tissue damage, fibrosis and dysfunction. These events augment the blood pressure elevations in hypertension and promote end-organ damage. Factors that activate immune cells include sympathetic outflow, increased sodium within microenvironments where these cells reside, and signals received from the vasculature. In particular, the activated endothelium releases reactive oxygen species and interleukin (IL)-6 which in turn stimulate transformation of monocytes to become antigen presenting cells and produce cytokines like IL-1β and IL-23, which further affect T cell function to produce IL-17A. Genetic deletion or neutralization of these cytokines ameliorates hypertension and end-organ damage. In this review, we will consider in depth features of the hypertensive milieu that lead to these events and consider new treatment approaches to limit the untoward effects of inflammation in hypertension.

Abstract MP28: A New Gut Microbial Metabolite Derived From Low Fibre Intake

Low fermentable fibre intake has emerged as an important risk factor for hypertension through changes in the gut microbiota, but the biological pathways and specific metabolites involved are unknown. We performed untargeted liquid-chromatography mass spectrometry metabolomic profiling on plasma samples from 16 mice fed low or high fibre diets and 70 participants with ambulatory blood pressure recordings. Mouse gut microbiome was analysed using 16S rRNA gene sequencing . In vitro experiments were performed in human peripheral blood mononuclear cells (PBMCs) to assess the role of a new metabolite in inflammatory responses. The phenylalanine, tyrosine and tryptophan biosynthesis pathway was upregulated in hypertensive compared to normotensive participants, as well as in low compared to high fibre fed mice (both q <0.05, pathway impact factor=1.0). In particular, p-cresol glucuronide (pCG), an end-product of tyrosine metabolism, was higher in mice fed with low compared to high fibre in both angiotensin II-treated ( q =4.83 x10 -4 , fold change= 88) and sham groups ( q =1.56 x10 -4 , fold change= 297). pCG is derived from p-Cresol, which is produced by the gut microbiota. β-diversity analyses showed that distinct gut microbiome compositions were associated with levels of pCG in plasma (q<0.05). While diet had a major effect on the gut microbiome (~30%), we found that pCG levels were associated with 5.7-6.3% of the total gut microbiome variation. This is relevant as pCG’s precursor, p-cresol, may inhibit the growth of certain types of bacteria. To understand the possible role of pCG in hypertension, human PBMCs obtained commercially were treated with physiological levels of pCG for 24 hours. This resulted in an increase in proinflammatory IL-17A mRNA ( P =0.01, fold change= 1.79) and a decrease in anti-inflammatory IL-10 mRNA ( P =0.014, fold change= -2.32) when compared to untreated and mock-treated cells. In conclusion, tyrosine biotransformation was associated with both human hypertension and low fibre intake. pCG, a key microbial metabolite derived from the metabolism of tyrosine, was associated with distinct gut microbiome compositions and modulated inflammatory response, suggesting it may be involved in the genesis of hypertension.

Abstract P131: Jak2 Expression In Cd11c+ Myeloid Cells Plays A Role In Salt-sensitive Hypertension Through An Enac-dependent Mechanism.

Hypertension is a major risk factor for development of cardiovascular disease. Excess dietary salt contributes to inflammation and the genesis of hypertension. We recently found that gamma and alpha subunits of the epithelial sodium channel (ENaCαγ) on dendritic cells mediate NADPH oxidase-dependent formation of immunogenic isolevuglandin (IsoLG)-protein adducts leading to inflammation and salt-sensitive hypertension. We hypothesized that Jak2 expression, specifically in CD11c + myeloid cells, regulates expression of ENaCγ and promotes salt-sensitive hypertension. Our results indicate that deletion of Jak2 in CD11c + myeloid cells reduced the salt-induced expression of ENaCγ in CD11c+ cells. Moreover, mice lacking Jak2 in CD11c+ cells developed a blunted hypertensive response (123.8±4.7) during the high salt feeding phase of the N-Nitro-L-arginine methyl ester hydrochloride (L- NAME)/high salt model of salt-sensitive hypertension compared to their wildtype littermate controls (140.5±6.5). These mice also exhibited less infiltration of monocyte/macrophages in their kidneys and less volume retention (69.55±5.8) in response to high salt-feeding when compared to the wildtype litter mate controls (57.89±9.5). These results indicate that Jak2 expression in CD11c + myeloid cells plays a role in salt- sensitive hypertension through an ENaC-dependent mechanism.

The role of adverse occupational factors in the formation of hypertension in workers

Studied 147 male workers exposed to a complex of unfavorable production factors (noise, local vibration, fibrogenic aerosols, static and dynamic loads) were evaluated occupational hazards categorical. Among the studied professional factors, the significance of noise in the Genesis of hypertension was established

Моделювання артеріальної гіпертензії шляхом тривалого сольового навантаження. Моніторинг функціонування серцево-судинної системи та динаміки інтегральних показників життєдіяльності в щурів (частина II)

Запропоновано нову модель артеріальної гіпертензії (АГ), індуковану тривалим сольовим навантаженням. Розробка такої моделі базується на ролі натрію хлориду у функціонуванні життєво важливих органів і систем, у генезі АГ та її судинних порушень. Недостатня вивченість механізмів розвитку сольової АГ, фазності та тривалості патологічного стану за умов продовження сольового навантаження на тривалий час (до декількох місяців), особливостей дії різних лікарських засобів на тлі підвищеного споживання солі, стану серцево-судинної системи та інтегральних показників життєдіяльності зумовили мету дослідження. Мета дослідження – вивчити стан серцево-судинної системи та динаміку інтегральних показників життєдіяльності в білих щурів за формування АГ шляхом тривалого сольового навантаження. Формування нової моделі АГ забезпечувалося сольовим навантаженням щурів упродовж 81 доби за умов заміни води на 1 % розчин натрію хлориду з вільним доступом тварин до пиття. За проведення динамічних досліджень встановлено, що модель АГ характеризується суттєвим підвищенням артеріального тиску на 10–18 % у самиць і на 14–36 % у самців, про що свідчать зміни зазначеного показника в різні терміни від початку до 81 доби сольового навантаження. Значне зростання артеріального тиску спостерігалося в 54,5–66,6 % тварин упродовж 60 діб від початку сольового навантаження, водночас кількість тварин з підвищеним артеріальним тиском знижувалася до 23,6 % через 81 добу від початку сольового навантаження. Продовження сольового навантаження понад 21 добу характеризувалося розвитком брадикардії. Збільшення терміну сольового навантаження в щурів не призводило до суттєвої зміни інтегральних показників життєдіяльності різних органів і систем, патологічної зміни маси тіла тварин і коефіцієнтів маси внутрішніх органів, у тому числі тимуса. За формування АГ на 18–30 % знижувалася больова чутливість у щурів і спостерігався набряк кінцівок (суглобів і м’яких тканин стоп), що зростав з тривалістю сольового навантаження й перевищував значення в інтактних тварин понад 21 % через 81 добу від початку формування моделі АГ. Запропонована модель АГ відрізняється простотою формування, економічністю, досягненням відповідного ефекту в значної кількості щурів різної статі, можливістю відбору тварин з підвищеним артеріальним тиском на будь-якому етапі формування патологічного процесу, можливістю їхнього утримання за звичайних лабораторних умов, відсутністю загибелі тварин. Формування моделі АГ шляхом тривалого сольового навантаження не потребує спеціальної підготовки фахівців. Модель АГ за тривалого сольового навантаження пропонується для дослідження специфічної фармакологічної ефективності (гіпотензивної дії) і безпечності новосинтезованих сполук і відомих ліків за умов їхнього тривалого застосування.

POSSIBLE ROLE OF THE SPLEEN IN THE DEVELOPMENT OF HYPERTENSION IN HUMANS

Objective: Immune system (in particular T lymphocytes) is involved in the pathogenesis of arterial hypertension and microvascular remodelling. It has also been recently suggested a crucial role for spleen in the development and onset of hypertension, through a neuroimmune mechanism mediated by a splenic factor, the Placental growth factor (PIGF), in different models of experimental hypertension (Carnevale D, et al Immunity 2014, Carnevale D, et al. Nat Commun. 2016, Perrotta M, et al. Cardiovasc Res. 2018). However, to date no data are present in humans.Design and method: We investigated 29 patients: 19 were previously splenectomized for idiopathic thrombocytopenic purpura or marginal lymphoma (clinical conditions associated with good survival) and 10 patients underwent an elective surgical intervention (cholecystectomy) in the same period, well matched for ages, sex and cardiovascular risk factors. In all patients clinical and 24-hours blood pressure (BP) were recorded. Wall to lumen ratio of retinal arterioles (WLR) was obtained by Adaptive Optics as index of microvascular damage. Functional (basal) and structural (total) capillary density were studied by capillaroscopy before and after venous congestion. Results: The groups did not present statistically significant differences for clinical or 24-hours BP values (Clinical BP: 126.94 ± 8.20/72.38 ± 13.7 mmHg in splenectomized patients vs 125.56 ± 12.9/76.67 ± 5.59 mmHg in the cholecystectomized patients, p = NS; 24-hours BP: 119.7 ± 13.8/66.4 ± 6.60 vs 119.20 ± 8.76/69.10 ± 7.53 mmHg respectively, p = NS). No differences in central BP and Augmentation index were observed between the groups. Retinal arteriole morphology and capillary density did not differ between the groups. However, WLR was slightly higher, albeit not significant, in cholecystectomized than in splenectomized patients (Table). Conclusions: Our preliminary data did not confirm in humans the hypothesis of a difference in blood pressure values and indices of microvascular damage in splenectomized patients compared to cholecystectomized patients. However, a statistically not significant trend towards a greater WLR was observed in cholecystectomized patients. For a definitive conclusion about the involvement of the spleen in the genesis of hypertension also in humans it is necessary to extend the evaluation to a larger population.

The association of family history of hypertension and overweight induced early impairment in markers of oxidative stress and in heart rate variability

Considering the high prevalence of hypertension worldwide and the changes in lifestyle, the understanding of the mechanisms involved in the genesis of hypertension are important to reach more precise interventions. Our objective was to evaluate cardiovascular, autonomic and oxidative stress parameters in individuals with family history of hypertension (FH) with or without overweight. We performed a cross‐sectional study and selected 65 healthy sedentary men (24.08 ± 5.84 years) distributed into 4 groups: negative FH eutrophic (FNE, n=18) or with overweight (FNO, n=19) and positive FH eutrophic (FHE, n=17) or with overweight (FHO, n=17). The heart rate variability (HRV) was analyzed at rest by spectral analysis. The oxidative stress markers were evaluated in plasma. A positive correlation between levels LDL and WC/HC ratio was demonstrated (r: 0.54 p = 0.003) in FHE and FHO groups. We observed an increase in diastolic blood pressure in the FHO and FNO groups in relation to the FNE and FHE groups (p = 0.010). When we evaluated the cardiac sympathetic modulation (LF‐PI), we observed a significant increase in the FNO and FHO groups when compared to the FNE group (p = 0.0001). Furthermore, the FHO (2.30 ± 0.8) and FHE groups (2.52 ± 1) presented higher cardiac sympato‐vagal balance (LF/HF) compared to FNO (1.85 ± 0.67) and FNE groups (2.01 ± 0.84) (p =0.04). We observed an increase in systemic hydrogen peroxide concentration in the FHO group when compared to the other groups (p=0.003). Moreover, there was an increase in NADPH oxidase in plasma in FNO and FHO groups in relation the FNE and FHE groups (p = 0.04). In addition, there was an increase in plasma nitrite levels in FHO group compared to FNO, FNE and FHE groups (p=0.01). In conclusion our findings demonstrated that despite young and apparently healthy, the group with overweight and FH showed early impairment in HRV and in markers of oxidative stress. In addition, this group presented all dysfunctions observed in the presence of these risk factors alone, which may be associated with increased cardiovascular risk and target organ damage in this population.Support or Funding InformationUNINOVE, CNPq, CAPES, FAPESP.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

A Novel Mechanism of Renal Microcirculation Regulation: Connecting Tubule-Glomerular Feedback.

In this review, we summarized the current knowledge of connecting tubule-glomerular feedback (CTGF), a novel mechanism of renal microcirculation regulation that integrates sodium handling in the connecting tubule (CNT) with kidney hemodynamics. Connecting tubule-glomerular feedback is a crosstalk communication between the CNT and the afferent arteriole (Af-Art), initiated by sodium chloride through the epithelial sodium channel (ENaC). High sodium in the CNT induces Af-Art vasodilation, increasing glomerular pressure and the glomerular filtration rate and favoring sodium excretion. CTGF antagonized and reset tubuloglomerular feedback and thus increased sodium excretion. CTGF is absent in spontaneous hypertensive rats and is overactivated in Dahl salt-sensitive rats. CTGF is also modulated by angiotensin II and aldosterone. CTGF is a feedback mechanism that integrates sodium handling in the CNT with glomerular hemodynamics. Lack of CTGF could promote hypertension, and CTGF overactivation may favor glomerular damage and proteinuria. More studies are needed to explore the alterations in renal microcirculation and the role of these alterations in the genesis of hypertension and glomerular damage in animals and humans. • CTGF is a vasodilator mechanism that regulates afferent arteriole resistance. • CTGF is absent in spontaneous hypertensive rats and overactivated in Dahl salt-sensitive rats. • CTGF in excess may promote glomerular damage and proteinuria, while the absence may participate in sodium retention and hypertension.

Loss of Salt Sensing Kinase, SGK1, in T cells abrogates Memory Cell Formation, Hypertension and End‐Organ Damage

Accumulating evidence indicates that high salt‐intake, aging and hypertension promote NaCl accumulation in tissues. Elevated NaCl has been shown to promote TH17 cell formation in an SGK1‐dependent fashion. We have previously shown that memory T cells play a major role in the genesis of hypertension. These long‐lived cells remain responsive to repeated hypertensive stimuli, such as repeated salt feeding, and can be mobilized to enter the kidney where they release cytokines that promote renal dysfunction. To examine mechanisms by which T cells sense salt and contribute to salt‐sensitivity, we tested the hypothesis that SGK1 in T cells is necessary for formation of memory T cells and their activation in salt‐sensitive hypertension. We produced mice with T cell specific deletion of SGK1, SGK1fl/fl × tgCD4cre mice and used SGK1fl/fl mice as controls. To impose repeated episodes of hypertension, we treated these mice with L‐NAME (0.5mg/ml) in drinking water for two weeks, allowed a two‐week normotensive interval and a then fed high salt (4% NaCl) for three weeks. L‐NAME followed by high salt increased memory T cells in the kidney, aorta and bone marrow of SGK1fl/fl control mice but not in SGK1fl/fl × tgCD4cre mice, as identified by the surface marker CD44hi. To assess markers of renal injury, we measured albumin in 24‐hour urine samples collected at the end of the L‐NAME/high salt. L‐NAME/high salt caused striking albuminuria in SGK1fl/fl mice and this was prevented in SGK1fl/fl × tgCD4cre mice. In additional studies, we found that loss of SGK1 in T cells abrogates renal and vascular inflammation and protects against hypertensive renal and vascular injury in the L‐NAME/high salt model. Thus, our data indicate that SGK1 in T cells promotes their development of salt sensitivity and mediates their ability to cause renal and vascular dysfunction in hypertension.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Daily sodium intake influences the relationship between angiotensin-converting enzyme gene insertion/deletion polymorphism and hypertension in older adults.

The angiotensin-converting enzyme insertion/deletion (I/D) gene polymorphism has been widely reported as being associated with hypertension; however, most studies do not consider environmental/behavioral factors. This study aimed to investigate the relationship among angiotensin-converting enzyme insertion/deletion gene polymorphism, environmental/behavioral factors, and hypertension in community-dwelling elderly individuals. All community-dwelling older adults from Aiquara, Bahia, Brazil, were invited to take part in this study. After exclusions, 234 elderly participants were submitted to a data collection, which included sociodemographics, lifestyle and health status questionnaires, clinical assessment, and blood withdrawal. From the blood samples, the gene polymorphism was identified through polymerase chain reaction and patients grouped as II or D allele carriers (ID and DD genotypes). Hypertension was defined by self-report of the condition and confirmed by antihypertensive drug treatment. Chi-square test was used to identify differences in the proportions distributed between groups of each dependent variable (ie, genotype, diagnosis of hypertension, and blood pressure state from medicated patients with hypertension). The prevalence of hypertension was 59.3% and was associated with diabetes mellitus and obesity, but not with angiotensin-converting enzyme insertion/deletion gene polymorphism. However, carriers of the II genotype, a salt-sensitivity genotype, exhibited a significantly greater estimated sodium intake. In addition, among medicated elderly patients with hypertension, II genotype carriers exhibited poor blood pressure control, despite similar antihypertensive drug treatment in D allele carriers, while exhibiting a greater estimated sodium intake. Our results provide new evidence regarding the interaction of genetic and environmental/behavioral factors in the genesis of hypertension among elderly patients, as well as in blood pressure control in medicated elderly patients with hypertension.

Mechanisms and Subclinical Consequences of Aortic Stiffness.

The number of published articles on PubMed with arterial stiffness or aortic stiffness in the title during the past 20 years exceeds 4000 articles published, with more than one-half published in the past 5 years (see Figure). The studies published on the topic of arterial stiffness span the full translational continuum from basic mechanistic studies in cell and animal models to small experimental studies in humans and large observational cross-sectional and prospective studies relating arterial stiffness to subclinical target organ damage or clinical cardiovascular disease (CVD) events. The reason for this rapidly growing area of investigation is likely attributed to the strong body of evidence indicating that arterial stiffness, specifically aortic stiffness as measured by the reference standard carotid-femoral pulse wave velocity (CFPWV), is a robust predictor of clinical CVD events in adults even after adjusting for blood pressure (BP) and other conventional CVD risk factors.1,2 In addition, several prospective cohort studies suggest that elevated CFPWV precedes the development of incident hypertension in middle-aged adults,3,4 consistent with the idea that aortic stiffness may be causal in the genesis of hypertension with aging in humans rather than a subclinical consequence. Figure. The number of published articles in PubMed with the terms arterial+stiffness or aortic+stiffness appearing in the title during the past 20 y. In 2015, the American Heart Association published a comprehensive Scientific Statement addressing the nomenclature, methodologies, utility, limitations, and gaps in knowledge related to arterial stiffness to inform the research community of the state of field and help guide future directions for investigation, including identifying targets for intervention.5 Because the putative mechanisms that contribute to the development of aortic stiffness remain elusive, the current review article will focus on the recent advances during the past 2 to 3 years describing some novel mechanisms …

Abstract 102: Loss of Salt Sensing Kinase, SGK1, in T Cells Abrogates Memory T Cell Formation, Hypertension, and End-organ Damage

Accumulating evidence indicates that NaCl can be concentrated in tissues with high salt-intake, age and in the setting of hypertension. Elevated NaCl has been shown to promote T H 17 cell formation in an SGK1-dependent fashion. We have previously shown that Memory T cells play a major role in the genesis of hypertension. These long-lived cells remain responsive to repeated hypertensive stimuli, such as salt feeding, and can be mobilized to enter the kidney where they release cytokines that promote renal dysfunction. To examine mechanisms by which T cells sense salt and contribute to salt-sensitivity, we tested the hypothesis that SGK1 in T cells is necessary for formation of memory T cells and their activation in salt-sensitive hypertension. To study the role of SKG1 in hypertension, we produced mice with T cell specific deletion of SGK1, SGK1 fl/fl x tg CD4cre mice and used SGK1 fl/fl mice as controls. To impose repeated episodes of hypertension, we treated these mice with L-NAME (0.5mg/ml) in drinking water for two weeks, allowed a two-week normotensive interval and a then fed high salt (4% NaCl) for three weeks. L-NAME followed by high salt increased memory T cells in the kidney, aorta and bone marrow of SGK1 fl/fl control mice but not in SGK1 fl/fl x tg CD4cre mice, as identified by the surface marker CD44 hi . To assess markers of renal injury, we measured albumin in 24-hour urine samples collected at the end of the L-NAME/high salt. L-NAME/high salt caused striking albuminuria in SGK1 fl/fl mice and was absent in SGK1 fl/fl x tg CD4cre mice. In additional studies, we found that loss of SGK1 in T cells abrogates renal and vascular inflammation and protects against hypertensive renal and vascular injury in the L-NAME/high salt model. Thus, our data provide a potential mechanism by which SGK1 in T cells promotes their development of salt sensitivity and their mediation of renal and vascular dysfunction in hypertension.

Comparison of the role of the renin-angiotensin aldosterone system in the genesis of hypertension between two groups of nonhunting dogs and hunting dogs

The role of the renin-angiotensin aldosterone system in the genesis of hypertension between nonhunting dogs and hunting dogs of various breeds was comparatively studied in the city of Tuzla (Bosnia and Herzegovina). Sixty dogs were divided into four subgroups based on different age categories. Hypertension was recorded in 21 dogs or in 35% of examined dogs. Fourteen dogs had mild (23.3%), 5 dogs had moderate (8.3%), and 2 dogs had severe hypertension (3.3%). The most cases of hypertension (n = 9) were recorded in hunting dogs aged from 9 to 12 years. In subgroups of nonhunting and hunting dogs aged from 1 to 3 years, a high correlation was recorded between systolic and diastolic pressures (P < 0.0001). A certain degree of correlation was recorded between systolic pressure and renin (P = 0.037) and between heart rate and renin (P = 0.024). In subgroups of nonhunting and hunting dogs aged from 9 to 12 years, a high correlation was recorded between systolic and diastolic pressures (P = 0.006) and between diastolic pressure and heart rate (P = 0.002). A certain degree of correlation existed between systolic pressure and heart rate (P = 0.041), systolic pressure and aldosterone (P = 0.035), and heart rate and renin (P = 0.038). Increased values of renin were mostly recorded in dogs with hypertension. This research indicates the importance of routine blood pressure measurement during every examination, which can thus serve as a screening for undertaking further steps in processing the patient.

Dendritic cells and isolevuglandins in immunity, inflammation, and hypertension.

Hypertension is the major risk factor for morbidity and mortality from myocardial infarction, stroke, heart failure, and chronic kidney disease. Despite its importance, the pathogenesis of essential hypertension is poorly understood. During the past several years, it has become evident that T cells contribute to hypertension. Activated T cells accumulate in the perivascular space and the kidney and release cytokines that promote vascular dysfunction and end-organ damage. Although dendritic cells play a pivotal role in initiating adaptive immune responses, T cells have taken center stage in studies implicating the immune system in the genesis of hypertension. The mechanisms by which T cells are activated and the antigens involved are poorly understood. We recently showed that hypertension is associated with increased dendritic cell production of the TH17 polarizing cytokines, IL-6, IL-1β, and IL-23. This occurs in part by increased superoxide production via NADPH oxidase and protein modification by highly reactive isolevuglandins (IsoLGs). IsoLGs are produced via the isoprostane pathway of free radical-mediated lipid peroxidation and, when adducted to proteins, have the potential to act as neoantigens. In this review, we discuss recent advances in our understanding of the role of antigen-presenting dendritic cells in the pathophysiology of hypertension and highlight potential neoantigens that may contribute to this disease.

Abstract 091: High Salt Promotes Conversion of Human Monocytes Into Dendritic Cells via Formation of Immunogenic Isoketals

High salt intake and inflammation are implicated in the genesis of hypertension. Recently it has become clear that sodium can accumulate in the interstitial space in concentrations exceeding that of the plasma, and that these high salt (HS) concentrations can be pro-inflammatory. Our laboratory recently published a new pathway in which increased oxidative stress in dendritic cells (DCs) leads to formation of isoketal-modified proteins which act as neo-antigens to activate T cells. We hypothesized that increasing sodium chloride (NaCl) in excess activates antigen presenting cells via formation of immunogenic isoketals. We exposed monocytes from human volunteers to normal physiological NaCl (NS: 150 mM/L), elevated NaCl concentrations (HS: 190 mM/L), or an equiosmoloar concentration of mannitol. We found that exposure of human monocytes to high salt, but not mannitol, caused a 2-fold increase in formation of isoketal-modified proteins. This was associated with an increase in activation marker CD86 (NS: 466 ± 192 vs HS: 596 ± 324 MFI p&lt;0.05) and production of inflammatory cytokines IL-6, IL-β and TNF-α. Interestingly, these cells expressed surface markers indicative of transformation to DCs, as evidenced by their acquisition of surface marker CD83. In additional immunofluorescence studies, we found that monocytes exposed to HS for 7 days acquire a DC like morphology. Moreover, using flow cytometry, we confirmed that high salt exposure causes these cells to lose the monocyte marker CD14 (NS: 41.1 ± 15.4 vs HS: 19.9 ± 6.4 MFI; p&lt;0.05), and gain the DC marker CD209 (NS: 24.2 ± 1.0 vs HS: 49.3 ± 0.7 MFI; p&lt;0.001). None to these effects were mimicked by mannitol and scavenging of isoketals during high salt exposure. High salt dramatically increased mRNA expression of GM-CSF (NS: 758 ± 440.8 vs HS: 5476 ± 2268 MFI; p&lt;0.05), IL-4 NS: 1868 ± 560.6 vs HS: 4867 ± 1152 MFI; p&lt;0.05) and Flt3 (NS: 2526 ± 636.8 vs HS: 10014 ± 2370 MFI; p&lt;0.05), which are known to mediate monocyte conversion to DCs. Thus, we have defined a novel pathway whereby high NaCl concentrations lead to transformation of monocytes to DCs due to increased formation of immunogenic isoketals. These observations provide insight into how elevated sodium environments lead to an inflammatory state.

Ruminations About Renal Denervation.

Renal artery denervation has captured the imagination of cardiologists as few recent technologies have done.1 The underlying pathophysiological construct seemed persuasive because evidence of sympathetic overactivity in the genesis of hypertension and heart failure has been clearly documented. Moreover, initial nonrandomized studies using different catheter systems in patients with hypertension deemed treatment resistant almost uniformly found large drops in office blood pressure measurements. The initial assessment of those very impressive results was surprisingly noncritical in many parts of the world in which the procedure was adopted into clinical practice. Subsequently, the neutral results of the SYMPLICITY-HTN 3 trial (Renal Denervation in Patients With Uncontrolled Hypertension),2 which was the first to incorporate a “sham procedure” control arm, came as a stunning surprise to some and generated a wide spectrum of responses, including denial, disbelief, abrogation of the entire concept, a critique of several technical and operator-dependent issues, and an increasing awareness of the power of placebo, regression to the mean, and methods of assessing blood pressure control. As is so often the case after the initial furor, it is a time for sober reflection, and a more circumspect view of renal artery denervation has been adopted that in turn has led to the design of more sophisticated ongoing trials. Since the first studies, there is now a much greater understanding of resistant hypertension. Many of these lessons came from the SYMPLICITY HTN-3 trial.2 First, reports of the prevalence of resistant hypertension may have been greatly exaggerated. When studied rigorously, it appears that poor adherence is the root cause of the majority of cases initially felt to be resistant hypertension.3 The salutary role of aldosterone blockade in many instances of resistant hypertension has also now been fully appreciated. Partnership with dedicated hypertension experts based …

High Salt Activates Human Monocytes and Promotes their Conversion into Dendritic Cells via Formation of Immunogenic Isoketal‐adducts

High blood pressure is a major modifiable risk factor for cardiovascular disease (CVD) which is the leading cause of death worldwide. Excessive salt intake and inflammation are implicated in the genesis of hypertension. It has recently become evident that sodium accumulates in the interstitial space and can promote inflammation through poorly defined mechanisms. We recently published a new pathway in which increased oxidative stress in dendritic cells (DCs) leads to formation of isoketal‐modified proteins which act as neo‐antigens to activate T cells. We hypothesized that increasing sodium chloride (NaCl) in excess of the physiological interstitial space concentrations activates antigen presenting cells via formation of immunogenic isoketals. We exposed monocytes from human volunteers to normal physiological NaCl (150 mM/L), elevated NaCl concentrations (190 mM/L), or an equiosmoloar concentration of mannitol. We found that exposure of human monocytes to high salt, but not mannitol, caused a 2‐fold increase in formation of isoketal‐modified proteins. This was associated with an increase in activation marker CD86 (466 ± 192 normal salt vs 596 ± 324 high salt) and production of inflammatory cytokines IL‐6, IL‐β and TNF‐α. Interestingly, these cells expressed surface markers indicative of transformation to DCs, as evidenced by their acquisition of surface marker CD83. In additional immunofluorescence studies, we found that monocytes exposed to high salt for 7 days acquire a DC like morphology. Moreover, using flow cytometry, we confirmed that high salt exposure causes these cells to lose the monocyte marker CD14, and gain the DC marker CD209. When co‐cultured with T cells from the same patients, these cells drive T cell proliferation. Scavenging of isoketals during high salt exposure prevented conversion of monocytes into DCs and their ability to drive T cell proliferation. Thus, we have defined a novel pathway whereby high NaCl concentrations lead to transformation of monocytes to DCs due to increased formation of immunogenic isoketals. These observations provide insight into how elevated sodium environments lead to an inflammatory state.Support or Funding InformationThis work is supported by National Institutes of Health grants R01HL039006, P01HL058000, P01HL095070, P01GM015431, R01HL108701, R01HL105294, VITA award HHSN268201400010C and the Strategically Focused Research Network Award from the American Heart Association.