A Cross-Talk between the Renin-Angiotensin and Adrenergic Systems in Cardiovascular Health and Disease

It is well accepted that a number of cardiovascular (CV) and renal diseases are characterized by the long-term activation of both the renin-angiotensin system (RAS) and the sympathetic nervous system (SNS), which also contribute to the pathophysiology of structural and functional CV abnormalities as well as to the final clinical outcome. Moreover, there is a growing body of conclusive evidence that these systems do not operate independently, but interact at different levels throughout the CV system. The mediation of renin release from juxtaglomerular epithelioid (JGE) cells in kidney by SNS is well established and accepted. On the other hand, in recent years it became evident that RAS, by its main effect or angiotensin II (Ang II), induces SNS activity in various organs and tissues. Thus, there is a growing effort to clarify pathophysiological mechanisms of interaction and a more evident mutual potentiation of these two systems in different pathological states. Since it became evident that a high salt (HS) intake, which is a major risk factor for hypertension development, has a deleterious impact on vascular and endothelial functions (even in the absence of blood pressure changes), it became necessary to investigate and clarify the effect of HS loading on major regulating systems—RAS and SNS—precisely in healthy individuals. The present review aimed to summarize the interactions between the RAS and SNS in health and diseases (e.g. cardiovascular, renal), with a special focus on these two systems’ interaction during HS intake in a healthy normotensive population

The Markers of Endothelial Activation

Biomarkers are biological indicators of processes that are part of ethiopathogenesis of the diseases, and can, but do not have to be causal to diseases. One very important question is how specific and sensitive the marker is, since one molecule can appear in many conditions. Biomarkers of endothelial cell activation can be very diverse, from biochemical/metabolic to functional biomarkers. Activation of endothelial cells is part of physiological as well as pathophysiological response of cardiovascular system in conditions as physical activity, growth, pregnancy and in all cardiometabolic diseases (e.g., hypertension, diabetes mellitus, autoimmune inflammatory diseases, coronary artery disease, atherosclerosis, ischemia and reperfusion, etc.). During activation, there is a change in endothelial cell morphology and function, which could be a defensive response of endothelium to provoking factor or could lead to increased risk for the injury and end organ damage. This chapter aims to overview current knowledge on established biomarkers of normal and disease-related endothelial activation and to provide information on novel, potential biomarkers in common cardiometabolic diseases

Myeloperoxidase (MPO) and high sensitivity C-reactive protein (hsCRP) as inflammatory biomarkers of endothelial and leukocyte activation in overweight hypertensive patients

Background: Low-grade inflammation mediates the relation between overweight and the development of cardiovascular diseases. The study aimed to examine if myeloperoxidase (MPO) and hsCRP (high-sensitivity C-reactive protein) in overweight hypertensive patients can be used as biomarkers of endothelial and leukocyte activation. Material and methods: Seventy-five subjects were included in the study; 38 had essential arterial hypertension (AH) and 37 were normotensive controls (NC), subsequently divided into overweight (OW; BMI ≥ 25 kg/m2) and normal weight subgroups (NW; BMI < 25 kg/m2). Body mass index (BMI), inflammatory markers concentrations, association of MPO and hsCRP with AH and/or overweight were assessed. Results: AH patients had higher MPO (median 132.5 pmol/L, IQR: 53.8–691.9) (p < 0.001), while hsCRP did not significantly differ compared to normotensive controls (NC). NW-AH patients had higher MPO (p = 0.02) than normotensive NW patients. MPO was similar between normotensive patients OW and NW, while hsCRP concentration was significantly higher in the OW (median 1.85 mg/L, IQR: 0.47–7.19) (p = 0.01) compared to NW. OW-AH patients had significantly higher MPO (median 137.4 pmol/L, IQR: 53.80–703.4) (p = 0.002) compared to normotensive NW and OW (p < 0.001) patients, likely reflecting neutrophilic activation in hypertension. Additionaly, OW-AH patients had significantly higher hsCRP (median 1.71 mg/L, IQR: 0.22–14) (p = 0.005) than normotensive NW patients. hsCRP significantly positively correlated with BMI in both AH (r = 0.41, p = 0.009) and NC groups (r = 0.38, p = 0.01), while MPO did not correlate, supporting inflammation in OW, particularly in OW with AH. Conclusions: All together, the results suggest that inflammation may mediate mutual association of AH and OW, suggesting MPO as inflammatory biomarker for AH and hsCRP for overweight

The interplay between sympathetic overactivity, hypertension and heart rate variability (Review, invited)

The control of arterial pressure is a complex interaction of the long- and short-term influences of hormones, local vascular factors, and neural mechanisms. The autonomic nervous system and its sympathetic arm play important roles in the regulation of blood pressure, and overactivity of sympathetic nerves may have an important role in the development of hypertension and related cardiovascular disorders. The baroreceptor system opposes either increases or decreases in arterial pressure, and the primary purpose of the arterial baroreflex is to keep blood pressure close to a particular set point over a relatively short period of time. The ability of the baroreflex to powerfully buffer acute changes in arterial pressure is well established, but the role of the arterial baroreceptor reflex in long-term control of arterial pressure has been a topic of many debate and controversy for decades. The sympathetic nervous system and arterial baroreceptor reflex control of renal sympathetic nerve activity has been proposed to play a role in long-term control of arterial pressure. The aim of this paper has been to review the postulated role of sympathetic activation

The Effects of Arterial Blood Pressure Reduction on Endocan and Soluble Endothelial Cell Adhesion Molecules (CAMs) and CAMs Ligands Expression in Hypertensive Patients on Ca-Channel Blocker Therapy

Background/Aims: To determine the effect of arterial blood pressure (BP) reduction on endocan and soluble cell adhesion molecules' (sCAM) plasma concentration and expression of their ligands on circulatory leukocyte subpopulations. Methods: 24 hypertensive subjects of both sexes (age: 53±8 yrs) were treated with Ca-channel blocker, amlodipin (5-10 mg/day for 8 weeks; to reach BP≤139/89mmHg). The serum sCAMs and endocan concentrations were determined by ELISA kits. Level of ICAM/VCAM ligands on leukocytes was assessed by flow cytometry. Paired t-test, or t-test were used as appropriate, with Pearson's correlation calculated; pResults: sICAM-1 and sVCAM-1 were decreased (p≤0.001 and p=0.002, respectively), while E-selectin concentration was increased after amlodipin treatment (P=0.014). CD11a/LFA-1 (ICAM-1 and endocan ligand) was significantly increased in all three cell types with BP decrease. CD15 and CD49d/VLA-4 (VCAM-1 ligand) did not change after the treatment. There was significant positive correlation of systolic and diastolic BP with ICAM-1 and VCAM-1, and significant negative correlation of systolic BP with CD11a/LFA-1. Endocan significantly positively correlated with ICAM-1. Conclusions: The increased expression of ICAM/VACM ligands, together with decrease of sCAMs and endocan suggests the de-activation of endothelium with reduction in BP, decreasing the adherence of circulatory leukocytes to endothelium; subsequently decreasing the risk for development of atherosclerosis

Sex-specific differences in chromosome-dependent regulation of vascular reactivity in female consomic rat strains from a SS × BN cross

High-throughput studies in the Medical College of Wisconsin Program for Genomic Applications (Physgen) were designed to link chromosomes with physiological function in consomic strains derived from a cross between Dahl salt-sensitive SS/JrHsdMcwi (SS) and Brown Norway normotensive BN/NHsdMcwi (BN) rats. The specific goal of the vascular protocol was to characterize the responses of aortic rings from these strains to vasoconstrictor and vasodilator stimuli (phenylephrine, acetylcholine, sodium nitroprusside, and bath hypoxia) to identify chromosomes that either increase or decrease vascular reactivity to these vasoactive stimuli. Because previous studies demonstrated sex-specific quantitative trait loci (QTLs) related to regulation of cardiovascular phenotypes in an F2 cross between the parental strains, males and females of each consomic strain were included in all experiments. As there were significant sex-specific differences in aortic sensitivity to vasoconstrictor and vasodilator stimuli compared with the parental SS strain, we report the results of the females separately from the males. There were also sex-specific differences in aortic ring sensitivity to these vasoactive stimuli in consomic strains that were fed a high-salt diet (4% NaCl) for 3 wk to evaluate salt-induced changes in vascular reactivity. Differences in genetic architecture could contribute to sex-specific differences in the development and expression of cardiovascular diseases via differential regulation and expression of genes. Our findings are the first to link physiological traits with specific chromosomes in female SS rats and support the idea that sex is an important environmental variable that plays a role in the expression and regulation of genes

Reduced Dietary Selenium Impairs Vascular Function by Increasing Oxidative Stress in Sprague-Dawley Rat Aortas

This study aimed to determine whether low dietary Se content affects the function and mechanisms mediating the vascular relaxation of rat aortas, and to test the role of oxidative stress in observed differences. Male Sprague Dawley (SD) rats were maintained for 10 weeks on low Se (low-Se group; N = 20) or normal Se content (norm-Se group; N = 20) rat chow. Dose responses to acetylcholine (ACh; 10−9–10−5M) and the response to reduced pO2 were tested in noradrenaline-precontracted aortic rings in the absence/presence of the nitric oxide synthase (NOS) inhibitor nitro-l-arginine methyl ester (l-NAME), the cyclooxygenase 1 and 2 (COX-1, 2) inhibitor Indomethacin, and the antioxidative agent Tempol in tissue bath. mRNA expression of glutathione peroxidase 1 (GPx1), catalase (CAT), and Cu/Zn superoxide dismutase (SOD) was measured in rat aortas. Oxidative stress (Thiobarbituric Acid Reactive Substances; TBARS), antioxidative plasma capacity (ferric reducing ability of plasma assay; FRAP), and protein levels of GPx1 were measured in plasma and serum samples, respectively. Reduced ACh-induced relaxation (AChIR) (dominantly mediated by NO) in the low-Se group compared to the norm-Se group was restored by Tempol administration. Hypoxia-induced relaxation (HIR) (dominantly mediated by COX-1, 2), TBARS, and FRAP as well as GPx1 serum concentrations were similar between the groups. mRNA GPx1 expression in rat aortas was significantly decreased in the low-Se compared to the norm-Se group. These data suggest that low dietary Se content increases the local oxidative stress level, which subsequently affects the NO-mediated vascular response

Omega-3 Polyunsaturated Fatty Acids Enriched Hen Eggs Consumption Enhances Microvascular Reactivity in Young Healthy Individuals

Whilst the beneficial effect of omega-3 polyunsaturated fatty acids (PUFAs) supplementation on cardiovascular (CV) system is well supported in CV patients, the effect of consumption of omega-3 PUFAs enriched functional food in healthy individuals is still not fully elucidated. This study aimed to determine the effect of consumption of omega-3 PUFAs enriched hen eggs on microvascular reactivity (primary outcome), blood pressure (BP) and serum lipid profile in young healthy individuals. Control group (N=16) ate three ordinary hen eggs (277 mg omega-3 PUFAs/day), and OMEGA-3 group (N=20) ate three omega-3 PUFAs enriched eggs containing 259 mg of omega-3 PUFAs/egg daily (ALA 167 mg/egg, EPA 7 mg/egg, DHA 84 mg/egg) for 3 weeks (777 mg omega-3 PUFAs/day). Post-occlusive reactive hyperemia (PORH) in skin microcirculation assessed by laser Doppler flowmetry, serum lipid profile, fasting blood glucose, high-sensitivity C-reactive protein (hsCRP) and arterial BP were measured in all subjects before and after the protocol. PORH was significantly enhanced, and triglycerides, hsCRP and BP were significantly decreased in OMEGA-3 group compared to baseline measurement, while there was no significant difference in Control group after the protocol compared to baseline. This is the first study to demonstrate that consumption of a mixture of omega-3 PUFAs (ALA+EPA+DHA), provided via enriched hen eggs, elicits changes in microvascular reactivity, BP and triglycerides level in healthy subjects that are associated with CV benefits, thus suggesting that daily consumption of omega-3 PUFAs enriched eggs in healthy individuals may potentially contribute to CV risk factors attenuation and disease prevention.The accepted manuscript in pdf format is listed with the files at the bottom of this page. The presentation of the authors' names and (or) special characters in the title of the manuscript may differ slightly between what is listed on this page and what is listed in the pdf file of the accepted manuscript; that in the pdf file of the accepted manuscript is what was submitted by the author