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Journal ArticleDOI

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.
Citations
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Journal ArticleDOI
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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Journal ArticleDOI
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

Journal ArticleDOI
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

Journal ArticleDOI
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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Journal ArticleDOI
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

References
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Journal ArticleDOI
01 Jul 1998-Peptides
TL;DR: It is concluded that catestatin is a potent vasodilator in vivo whose actions appear to be mediated, at least in part, by histamine release and action at H1 receptors.

124 citations

Journal ArticleDOI
TL;DR: This study supports the hypothesis that the PPAR-gamma Pro12Ala polymorphism is protective against diabetes in Caucasians but not in South Asians.
Abstract: OBJECTIVE —To determine whether the peroxisome proliferator–activated receptor (PPAR)-γ Pro12ala polymorphism modulates susceptibility to diabetes in South Asians. RESEARCH DESIGN AND METHODS —South Asians ( n = 697) and Caucasians ( n = 457) living in Dallas/Forth Worth, Texas, and South Asians living in Chennai, India ( n = 1,619), were enrolled for this study. PPAR-γ Pro12Ala was determined using restriction fragment–length polymorphism. Insulin responsiveness to an oral glucose tolerance test (OGTT) was measured in nondiabetic subjects. RESULTS —The Caucasian diabetic subjects had significantly lower prevalence of PPAR-γ 12Ala when compared with the Caucasian nondiabetic subjects (20 vs. 9%, P = 0.006). However, there were no significant differences between diabetic and nondiabetic subjects with reference to the Pro12Ala polymorphism among the South Asians living in Dallas (20 vs. 23%) and in India (19 vs. 19.3%). Although Caucasians carrying PPAR-γ Pro12Ala had lower plasma insulin levels at 2 h of OGTT than the wild-type (Pro/Pro) carriers (76 ± 68 and 54 ± 33 μU/ml, respectively, P = 0.01), no differences in either fasting or 2-h plasma insulin concentrations were found between South Asians carrying the PPAR-γ Pro12Ala polymorphism and those with the wild-type genotype at either Chennai or Dallas. CONCLUSIONS —Although further replication studies are necessary to test the validity of the described genotype-phenotype relationship, our study supports the hypothesis that the PPAR-γ Pro12Ala polymorphism is protective against diabetes in Caucasians but not in South Asians.

124 citations


"Catestatin Gly364Ser Variant Alters..." refers result in this paper

  • ...This is similar to a previous study reporting that the 12Ala allele in the peroxisome proliferator– activated receptor-γ2 did not offer the same protective role in Indians as it did in Caucasians.60 Such contradictory associations of an allele provide evidence for heterogeneity in different populations and underscore the need for carrying out association studies in diverse ethnic populations to draw more accurate conclusions in each population....

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  • ...This is similar to a previous study reporting that the 12Ala allele in the peroxisome proliferator– activated receptor-γ2 did not offer the same protective role in Indians as it did in Caucasians.(60) Such contradictory associations of an allele provide evidence for heterogeneity in different populations and underscore the need for carrying out association studies in diverse ethnic populations to draw more accurate conclusions in each population....

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  • ...Of note, in a Southern Californian population, the 364Ser allele displayed association with diminished DBP levels, especially in men; however, the effect was not consistently observed for SBP or in women.39 Conversely, the 364Ser allele was associated with elevated SBP and MAP levels in a Japanese population (Table 2).59 Thus, 364Ser allele seems to exert directionally concordant effects on BP in several Asian populations (South Indian, North Indian, and Japanese) although not in Caucasians....

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Journal ArticleDOI
TL;DR: One peptide was characterized, which was named parastatin, that inhibited secretion of both PTH and CgA in a dose-dependent fashion over the range of 0.2-0.6 microM and extended the concept that C gA is a precursor of biologically active peptides.
Abstract: Chromogranin A (CgA), previously referred to as secretory protein- I, is a 50-kilodalton protein present in secretory granules of many endocrine and neuroendocrine cells. In the parathyroid it is present and cosecreted with PTH in response to hypocalcemia. CgA appears to be a precursor of bioactive peptides including pancreastatin, P-granin, vasostatin, and chromostatin. The presence of several highly conserved pairs of basic amino acids, putative cleavage sites, in the CgA molecule suggests that other yet unidentified bioactive peptides might exist within the molecule. We tested this speculation by subjecting porcine parathyroid CgA to digestion by endoproteinase Lys-C. Resulting CgA- derived peptides were isolated by reverse-phase Cl8 HPLC and tested for their ability to affect low-Ca*+ stimulated secretion by porcine parathyroid cells. We characterized one peptide, which we named parastatin, that inhibited secretion of both PTH and CgA in a dose- dependent fashion over the range of 0.2-0.6 pM. Parastatin migrated as a single band on sodium dodecyl sulfate-polyacrylamide gel electro- phoresis with an apparent mol wt of 11,000. Edman degradation yielded the sequence L-S-F-R-A-P-A-Y-G-F-R-G-P-G-L corresponding to res- idues 347-361 of porcine CgA. Amino acid analysis of endoproteinase Lys-C and endoproteinase Asp-N-generated fragments indicated that parastatin corresponds to residues 347-419 of CgA. A synthetic NH,- terminal fragment of rat parastatin corresponding to residues I-19 was as inhibitory as intact porcine parastatin on parathyroid gland secre- tion. These results extend the concept that CgA is a precursor of biologically active peptides. (Endocrinology 133: 461-466, 1993)

118 citations

Journal ArticleDOI
TL;DR: Gly364Ser was associated with lower diastolic blood pressure in 2 independent/confirmatory groups of patients with hypertension; genotype groups differed by ≈5 to 6 mm Hg, and the polymorphism accounted for ≈1.8% of population variance, although a significant gene-by-sex interaction existed, with an enhanced effect in men.
Abstract: BACKGROUND - Chromogranin A, coreleased with catecholamines by exocytosis, is cleaved to the catecholamine release-inhibitory fragment catestatin. We identified a natural nonsynonymous variant of catestatin, Gly364Ser, that alters human autonomic function and blood pressure. METHODS AND RESULTS - Gly364Ser heterozygotes and controls underwent physiological and biochemical phenotyping, including catecholamine production, chromogranin A precursor, and its catestatin product. Case-control studies replicated effects of the gene on blood pressure in the population. Gly364Ser displayed diminished inhibition of catecholamine secretion from cultured neurons. Gly/Ser heterozygotes displayed increased baroreceptor slope during upward deflections (by ≈47%) and downward deflections (by ≈44%), increased cardiac parasympathetic index (by ≈2.4-fold), and decreased cardiac sympathetic index (by ≈26%). Renal norepinephrine excretion was diminished by ≈26% and epinephrine excretion by ≈34% in Gly/Ser heterozygotes. The coalescent dated emergence of the variant to ≈70 000 years ago. Gly364Ser was in linkage disequilibrium with 1 major Chromogranin A promoter haplotype, although promoter haplotypes did not predict autonomic phenotypes. The 364Ser variant was associated with lower diastolic blood pressure in 2 independent/confirmatory groups of patients with hypertension; genotype groups differed by ≈5 to 6 mm Hg, and the polymorphism accounted for ≈1.8% of population diastolic blood pressure variance, although a significant gene-by-sex interaction existed, with an enhanced effect in men. CONCLUSIONS - The catestatin Gly364Ser variant causes profound changes in human autonomic activity, both parasympathetic and sympathetic, and seems to reduce risk of developing hypertension, especially in men. A model for catestatin action in the baroreceptor center of the nucleus of the tractus solitarius accounts for these actions.

110 citations

Journal ArticleDOI
TL;DR: A surprising pattern of CHGA variants is shown that alter the expression and function of this gene, both in vivo and in vitro, including rare alleles that qualitatively change the encoded product to alter the signaling potency ofCHGA-derived catecholamine release-inhibitory catestatin peptides.
Abstract: The chromogranin/secretogranin proteins are costored and coreleased with catecholamines from secretory vesicles in chromaffin cells and noradrenergic neurons. Chromogranin A (CHGA) regulates catecholamine storage and release through intracellular (vesiculogenic) and extracellular (catecholamine release–inhibitory) mechanisms. CHGA is a candidate gene for autonomic dysfunction syndromes, including intermediate phenotypes that contribute to human hypertension. Here, we show a surprising pattern of CHGA variants that alter the expression and function of this gene, both in vivo and in vitro. Functional variants include both common alleles that quantitatively alter gene expression and rare alleles that qualitatively change the encoded product to alter the signaling potency of CHGA-derived catecholamine release–inhibitory catestatin peptides.

109 citations


"Catestatin Gly364Ser Variant Alters..." refers background in this paper

  • ...Many functionally active DNA variants have been discovered in the promoter, coding and 3′-untranslated regions of the human CHGA gene.(7,18) Resequencing of the...

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  • ...Previous studies have discovered the occurrence of common SNPs in the CHGA promoter as well as coding regions.(18,19,39) Many of these SNPs have been found to be functionally active, either in altering the transcriptional activity of the promoter(18) or the potencies of the peptides they are found in....

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  • ...ise of providing small, yet important, clues in elucidating the mechanism for the development of hypertension.(18) However,...

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  • ...The minor alleles at -1018, -415, and -57 bp positions of the CHGA promoter give rise to one of the 5 common CHGA promoter haplotypes (GTTTGCCT) which shows higher promoter activity as compared with the WT consensus haplotype (GATTGTCC).(18) This would mean that the 364Ser carriers may have a more active promoter leading to greater levels of the parent CHGA molecule being produced....

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  • ...The 8 SNPs in the CHGA promoter form haplotypes which differ from each other in terms of their transcriptional activity.(18) The minor alleles at -1018, -415, and -57 bp positions of the CHGA promoter give rise to one of the 5 common CHGA promoter haplotypes (GTTTGCCT) which shows higher promoter activity as compared with the WT consensus haplotype (GATTGTCC)....

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