Catestatin Gly364Ser Variant Alters Systemic Blood Pressure and the Risk for Hypertension in Human Populations via Endothelial Nitric Oxide Pathway
TL;DR: CST-364Ser allele enhanced the risk for hypertension in human populations, possibly via diminished endothelial NO production because of altered interactions of CST-364 Ser peptide with ADRB2 as compared with CST-WT.
Abstract: Catestatin (CST), an endogenous antihypertensive/antiadrenergic peptide, is a novel regulator of cardiovascular physiology. Here, we report case–control studies in 2 geographically/ethnically distinct Indian populations (n≈4000) that showed association of the naturally-occurring human CST-Gly364Ser variant with increased risk for hypertension (age-adjusted odds ratios: 1.483; P =0.009 and 2.951; P =0.005). Consistently, 364Ser allele carriers displayed elevated systolic (up to ≈8 mm Hg; P =0.004) and diastolic (up to ≈6 mm Hg; P =0.001) blood pressure. The variant allele was also found to be in linkage disequilibrium with other functional single-nucleotide polymorphisms in the CHGA promoter and nearby coding region. Functional characterization of the Gly364Ser variant was performed using cellular/molecular biological experiments (viz peptide–receptor binding assays, nitric oxide [NO], phosphorylated extracellular regulated kinase, and phosphorylated endothelial NO synthase estimations) and computational approaches (molecular dynamics simulations for structural analysis of wild-type [CST-WT] and variant [CST-364Ser] peptides and docking of peptide/ligand with β-adrenergic receptors [ADRB1/2]). CST-WT and CST-364Ser peptides differed profoundly in their secondary structures and showed differential interactions with ADRB2; although CST-WT displaced the ligand bound to ADRB2, CST-364Ser failed to do the same. Furthermore, CST-WT significantly inhibited ADRB2-stimulated extracellular regulated kinase activation, suggesting an antagonistic role towards ADRB2 unlike CST-364Ser. Consequently, CST-WT was more potent in NO production in human umbilical vein endothelial cells as compared with CST-364Ser. This NO-producing ability of CST-WT was abrogated by ADRB2 antagonist ICI 118551. In conclusion, CST-364Ser allele enhanced the risk for hypertension in human populations, possibly via diminished endothelial NO production because of altered interactions of CST-364Ser peptide with ADRB2 as compared with CST-WT.
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TL;DR: This comprehensive overview is to provide an up-to-date insight into the distribution and properties of the well established granin-derived peptides and their putative roles in homeostatic regulations.
58 citations
Cites background from "Catestatin Gly364Ser Variant Alters..."
...WT-CST differs from its variant not only in the secondary structures, but also in the interactions with the β2-adrenergic receptor, suggesting that Gly364Ser-CST fails in binding to the β2-adrenergic receptor (Kiranmayi et al., 2016)....
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TL;DR: The CgA system, consisting of full‐length C gA and its fragments, is emerging as an important and complex player in cardiovascular, immunometabolic, and cancer regulation.
Abstract: Chromogranin A (CgA)-the index member of the chromogranin/secretogranin secretory protein family-is ubiquitously distributed in endocrine, neuroendocrine, and immune cells. Elevated levels of CgA-related polypeptides, consisting of full-length molecules and fragments, are detected in the blood of patients suffering from neuroendocrine tumors, heart failure, renal failure, hypertension, rheumatoid arthritis, and inflammatory bowel disease. Full-length CgA and various CgA-derived peptides, including vasostatin-1, pancreastatin, catestatin, and serpinin, are expressed at different relative levels in normal and pathological conditions and exert diverse, and sometime opposite, biological functions. For example, CgA is overexpressed in genetic hypertension, whereas catestatin is diminished. In rodents, the administration of catestatin decreases hypertension, cardiac contractility, obesity, atherosclerosis, and inflammation, and it improves insulin sensitivity. By contrast, pancreastatin is elevated in diabetic patients, and the administration of this peptide to obese mice decreases insulin sensitivity and increases inflammation. CgA and the N-terminal fragment of vasostatin-1 can enhance the endothelial barrier function, exert antiangiogenic effects, and inhibit tumor growth in animal models, whereas CgA fragments lacking the CgA C-terminal region promote angiogenesis and tumor growth. Overall, the CgA system, consisting of full-length CgA and its fragments, is emerging as an important and complex player in cardiovascular, immunometabolic, and cancer regulation.
50 citations
TL;DR: Key pathophysiological mechanisms of SNS derangement in HF are highlighted and integrative and up-to-date overview of diagnostic modalities such as SNS imaging methods and novel laboratory biomarkers that could aid in the assessment of the degree of S NS activation and provide reliable prognostic information among patients with HF are placed.
Abstract: Heart failure (HF) is a complex clinical syndrome characterized by the activation of at least several neurohumoral pathways that have a common role in maintaining cardiac output and adequate perfusion pressure of target organs and tissues. The sympathetic nervous system (SNS) is upregulated in HF as evident in dysfunctional baroreceptor and chemoreceptor reflexes, circulating and neuronal catecholamine spillover, attenuated parasympathetic response, and augmented sympathetic outflow to the heart, kidneys and skeletal muscles. When these sympathoexcitatory effects on the cardiovascular system are sustained chronically they initiate the vicious circle of HF progression and become associated with cardiomyocyte apoptosis, maladaptive ventricular and vascular remodeling, arrhythmogenesis, and poor prognosis in patients with HF. These detrimental effects of SNS activity on outcomes in HF warrant adequate diagnostic and treatment modalities. Therefore, this review summarizes basic physiological concepts about the interaction of SNS with the cardiovascular system and highlights key pathophysiological mechanisms of SNS derangement in HF. Finally, special emphasis in this review is placed on the integrative and up-to-date overview of diagnostic modalities such as SNS imaging methods and novel laboratory biomarkers that could aid in the assessment of the degree of SNS activation and provide reliable prognostic information among patients with HF.
43 citations
TL;DR: The importance of measuring total-CgA, full-length C gA, specific fragments, and their relative levels for a more thorough assessment of the pathophysiological function and diagnostic/prognostic value of the CgA system is discussed.
Abstract: Chromogranin A (CgA), a secretory protein released in the blood by neuroendocrine cells and neurons, is the precursor of various bioactive fragments involved in the regulation of the cardiovascular system, metabolism, innate immunity, angiogenesis, and tissue repair. After the original demonstration that circulating CgA can serve as a biomarker for a wide range of neuroendocrine tumors, several studies have shown that increased levels of CgA can be present also in the blood of patients with cardiovascular, gastrointestinal, and inflammatory diseases with, in certain cases, important diagnostic and prognostic implications. Considering the high structural and functional heterogeneity of the CgA system, comprising precursor and fragments, it is not surprising that the different immunoassays used in these studies led, in some cases, to discrepant results. Here, we review these notions and we discuss the importance of measuring total-CgA, full-length CgA, specific fragments, and their relative levels for a more thorough assessment of the pathophysiological function and diagnostic/prognostic value of the CgA system.
37 citations
Cites background from "Catestatin Gly364Ser Variant Alters..."
...Recently, the catestatin Gly364Ser allele was associated with enhanced risk for hypertension in Indian and Japanese populations [18, 54]....
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TL;DR: Catestatin is a chromogranin A‐derived peptide with a wide spectrum of biological activities, such as inhibiting catecholamines release, decreasing blood pressure, stimulating histamine release, reducing beta‐adrenergic stimulation, and regulating oxidative stress.
Abstract: Background Catestatin is a chromogranin A-derived peptide with a wide spectrum of biological activities, such as inhibiting catecholamine release, decreasing blood pressure, stimulating histamine release, reducing beta-adrenergic stimulation, and regulating oxidative stress. Objectives The aims of our study were to determine serum catestatin concentrations in obese children and adolescents in regard to presence or absence of metabolic syndrome (MS) and to evaluate the possible relations between catestatin levels and other cardiovascular risk factors. Subjects Ninety-two obese subjects with a body mass index z score > 2, aged 10 to 18 years, and 39 healthy, normal weight controls were enrolled in the study. Methods Serum catestatin concentrations were measured using an enzyme-linked immunosorbent assay. Results Significantly lower serum catestatin concentrations were recorded in the group of obese subjects compared with a control group (10.03 ± 5.05 vs 13.13 ± 6.25 ng/mL, P = 0.004). Further analyses revealed significantly lower catestatin concentrations in the subgroup of obese patients with MS (9.02 ± 4.3 vs 10.54 ± 5.36 vs 13.13 ± 6.25, P = 0.008). Serum catestatin concentrations were significantly negatively correlated with diastolic blood pressure (r = -0.253, P = 0.014), homeostatic model assessment of insulin resistance (r = -0.215, P = 0.037) and high sensitivity C-reactive protein (r = -0.208, P = 0.044). Conclusions To the best of our knowledge, this study is the first to report catestatin concentrations in obese children and adolescents and their possible relations with MS and cardiovascular risk factors in a pediatric population. Obese subjects with MS have lower serum catestatin concentrations than obese subjects without MS and controls.
21 citations
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TL;DR: It is concluded that plasma chromogranin A displays substantial heritability and is increased in established essential hypertension, and its elevation in established hypertension is associated with evidence of increased vesicular stores of the protein and with adrenergic hyperactivity.
Abstract: Multiple heritable traits are associated with essential (genetic) hypertension in humans. Because chromogranin A is increased in both human and rodent genetic hypertension, we examined the influence of heredity and blood pressure on chromogranin A in humans. In estimates derived from among- and within-pair variance in monozygotic versus dizygotic twins, plasma chromogranin A displayed significant (F 15,18 =2.93, P =.016) genetic variance (ς 2 g ), and its broad-sense heritability was high ( h 2 B =0.983). Plasma chromogranin A was increased in essential hypertension (99.9±6.7 versus 62.8±4.7 ng/mL, P
107 citations
TL;DR: CgA is an independent predictor of long-term mortality and heart failure hospitalizations across the spectrum of ACSs and provides incremental prognostic information to conventional cardiovascular risk markers.
Abstract: During the past decade, major progress has been made in the management of patients with acute coronary syndromes (ACSs). In parallel with advances in medical therapy and increasing use of an early invasive strategy, there has been focus on early risk stratification of patients, and in particular, the potential prognostic utility of circulating biomarkers.1 Currently, cardiac-specific troponins and B-type natriuretic peptide are the major routinely measured circulating biomarkers in patients with ACSs.2,3
Chromogranin A (CgA) is a 439 amino acid, 49 kDa polypeptide, which has been identified throughout the endocrine and nervous systems.4 Markedly elevated plasma levels have been observed in patients with neuroendocrine tumours,5 such as pheochromocytoma6 and carcinoid,7 and the clinical application of CgA measurements has so far been limited to diagnosis and follow-up of patients with such tumours. However, circulating CgA levels also correlate closely with increased sympathetic activity both in the adrenal medulla and the peripheral nerve endings,8–10 suggesting that circulating CgA may integrate neuroendocrine signals from various sources and thus represent an index of overall neuroendocrine activity. Moreover, myocardial production of CgA in humans with dilated and hypertrophic cardiomyopathy has recently been demonstrated,11 and CgA has been shown to increase in proportion to clinical severity and to be associated with prognosis in patients with both chronic and post-infarction heart failure.12,13 In a small population with predominantly ST-elevation myocardial infarction (MI), we have previously reported a univariable association between CgA levels and long-term survival,14 but because of modest study power, it remains unclear whether CgA is an independent predictor of survival. In patients with unstable angina and non-ST-elevation MI, no prognostic data are currently available. Because increased neuroendocrine activity may be related to potentially harmful pathophysiological processes in patients with both ST-elevation and non-ST-elevation ACS, including endothelial dysfunction and activation of pro-inflammatory cytokines, we hypothesized that circulating CgA levels would be predictive of the incidence of death and non-fatal cardiovascular events across the spectrum of ACS and would provide prognostic information independently of conventional risk markers, including objective measures of left ventricular dysfunction and contemporary cardiac biomarkers.
107 citations
TL;DR: The role of FTO in obesity predisposition among Chinese, Malays and Indians, the three major Asian ethnic groups, is confirmed and it is likely that Europeans and Asians share some of the genetic predisposition to obesity.
Abstract: Recent genome-wide association studies (GWAS) have identified 38 obesity-associated loci among European populations. However, their contribution to obesity in other ethnicities is largely unknown. We utilised five GWAS (N=10 482) from Chinese (three cohorts, including one with type 2 diabetes and another one of children), Malay and Indian ethnic groups from Singapore. Data sets were analysed individually and subsequently in combined meta-analysis for Z-score body-mass index (BMI) associations. Variants at the FTO locus showed the strongest associations with BMI Z-score after meta-analysis (P-values 1.16 × 10−7–7.95 × 10−7). We further detected associations with nine other index obesity variants close to the MC4R, GNPDA2, TMEM18, QPCTL/GIPR, BDNF, ETV5, MAP2K5/SKOR1, SEC16B and TNKS/MSRA loci (meta-analysis P-values ranging from 3.58 × 10−4–1.44 × 10−2). Three other single-nucleotide polymorphisms (SNPs) from CADM2, PTBP2 and FAIM2 were associated with BMI (P-value ⩽0.0418) in at least one dataset. The neurotrophin/TRK pathway (P-value=0.029) was highlighted by pathway-based analysis of loci that had statistically significant associations among Singaporean populations. Our data confirm the role of FTO in obesity predisposition among Chinese, Malays and Indians, the three major Asian ethnic groups. We additionally detected associations for 12 obesity-associated SNPs among Singaporeans. Thus, it is likely that Europeans and Asians share some of the genetic predisposition to obesity. Furthermore, the neurotrophin/TRK signalling may have a central role for common obesity among Asians.
95 citations
"Catestatin Gly364Ser Variant Alters..." refers background in this paper
...irrational to generalize the magnitude and direction of allelic effect sizes across populations.(53,54) A study in the Population...
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TL;DR: The modest correlations, differing risk estimates, and considerable between-association heterogeneity suggest that differential ancestral effects can be anticipated and genomic risk markers may need separate further evaluation in different ancestry groups.
Abstract: It is not well known whether genetic markers identified through genome-wide association studies (GWAS) confer similar or different risks across people of different ancestry. We screened a regularly updated catalog of all published GWAS curated at the NHGRI website for GWAS-identified associations that had reached genome-wide significance (p ≤ 5 × 10(-8)) in at least one major ancestry group (European, Asian, African) and for which replication data were available for comparison in at least two different major ancestry groups. These groups were compared for the correlation between and differences in risk allele frequencies and genetic effects' estimates. Data on 108 eligible GWAS-identified associations with a total of 900 datasets (European, n = 624; Asian, n = 217; African, n = 60) were analyzed. Risk-allele frequencies were modestly correlated between ancestry groups, with >10% absolute differences in 75-89% of the three pairwise comparisons of ancestry groups. Genetic effect (odds ratio) point estimates between ancestry groups correlated modestly (pairwise comparisons' correlation coefficients: 0.20-0.33) and point estimates of risks were opposite in direction or differed more than twofold in 57%, 79%, and 89% of the European versus Asian, European versus African, and Asian versus African comparisons, respectively. The modest correlations, differing risk estimates, and considerable between-association heterogeneity suggest that differential ancestral effects can be anticipated and genomic risk markers may need separate further evaluation in different ancestry groups.
92 citations
"Catestatin Gly364Ser Variant Alters..." refers background in this paper
...irrational to generalize the magnitude and direction of allelic effect sizes across populations.(53,54) A study in the Population...
[...]
TL;DR: It is reported that serum levels of chromogranin A, the major secretory granule matrix protein in neuroendocrine cells, are elevated in patients with heart failure and provides independent prognostic information, i.e. within a given NYHA class, patients with chromog Granin A levels above the median have a worse prognosis than patients with ChromogranIn A levels below the median.
Abstract: Since the initial demonstration of increased circulating norepinephrine in patients with chronic heart failure, a large number of investigations on neuroendocrine activation in heart failure have followed. It is now clear that persistent activation of neuroendocrine systems, notably the adrenergic system and the renin–angiotensin system is maladaptive in heart failure (reviewed in). In this issue, Ceconi et al. report that serum levels of chromogranin A, the major secretory granule matrix protein in neuroendocrine cells, are elevated in patients with heart failure. The increases in chromogranin A serum levels are related to decreasing functional status and provide independent prognostic information, i.e. within a given NYHA class, patients with chromogranin A levels above the median have a worse prognosis than patients with chromogranin A levels below the median. As with many novel observations, the work by Ceconi et al. raises many questions and leaves room for imagination. Therefore, let us take a closer look at chromogranin A from a cardiologist’s standpoint. Chromogranin A, a protein initially described in catecholamine storage vesicles of the adrenal medulla, has a widespread distribution in secretory vesicles throughout the endocrine, neuroendocrine and nervous system, where it is co-localized and co-secreted with the respective peptide or amine hormone. Chromogranin A plays a pivotal role in the process of hormone packaging and secretory granule formation. Importantly, chromogranin A also functions as a multipurpose prohormone. The primary structure of chromogranin A contains several pairs of basic amino acids that represent proteolytic cleavage sites for the generation of a number of biologically active peptides. Proteolysis of chromogranin A takes place in a tissue-specific manner both within secretory granules and after secretion into the extracellular space. An emerging functional pattern is that such chromogranin A-derived peptides inhibit further hormone release from the (neuro)endocrine cell of origin. For example, in catecholaminergic cells, proteolytic processing of chromogranin A liberates catestatin, a peptide with catecholamine secretion–inhibitory and vasodilating activities. Among the many chrom-
90 citations