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
References
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TL;DR: It is shown that Cts immunoreactivity is colocalized with tyrosine hydroxylase in C1 neurons of the rostral ventrolateral medulla of the RVLM and plays an important regulatory role in adaptive reflexes.
Abstract: The fundamental role and corollary effects of neuropeptides that govern cardiorespiratory control in the brain stem are poorly understood. One such regulatory peptide, catestatin [Cts, human chromo...
33 citations
"Catestatin Gly364Ser Variant Alters..." refers background in this paper
...The primary evidence for this was found when the administration of exogenous CST resulted in the rescue of the hypertensive and hyperadrenergic phenotypes exhibited by CHGA knockout mice.17,48 The role of CST as a potent vasodilator in vivo has also been well documented both in rats49 and in humans.50 CST also seems to be capable of modulating the components of the brain-stem circuitry (rostral and caudal ventrolateral medulla) that regulate BP.51,52...
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...It is well established that the endothelium plays an important role in regulating arterial BP....
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...components of the brain-stem circuitry (rostral and caudal ventrolateral medulla) that regulate BP.(51,52) Figure 5....
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TL;DR: The results suggest that catestatin plays an important role in central cardiorespiratory control in urethane-anesthetized, bilaterally vagotomized, artificially ventilated Sprague-Dawley rats.
Abstract: Hypertension is a major cause of morbidity. The neuropeptide catestatin [human chromogranin A-(352–372)] is a peptide product of the vesicular protein chromogranin A. Studies in the periphery and i...
30 citations
"Catestatin Gly364Ser Variant Alters..." refers background in this paper
...It is well established that the endothelium plays an important role in regulating arterial BP....
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...components of the brain-stem circuitry (rostral and caudal ventrolateral medulla) that regulate BP.(51,52) Figure 5....
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...The primary evidence for this was found when the administration of exogenous CST resulted in the rescue of the hypertensive and hyperadrenergic phenotypes exhibited by CHGA knockout mice.17,48 The role of CST as a potent vasodilator in vivo has also been well documented both in rats49 and in humans.50 CST also seems to be capable of modulating the components of the brain-stem circuitry (rostral and caudal ventrolateral medulla) that regulate BP.51,52...
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TL;DR: Accumulated evidence establishes CHGA as a novel susceptibility gene for EH, which acts as a prohormone giving rise to bioactive peptides such as vasostatin-I and catestatin that exhibit several cardiovascular regulatory functions.
Abstract: Chromogranin A (CHGA) is ubiquitously expressed in secretory cells of the endocrine, neuroendocrine, and neuronal tissues. Although this protein has long been known as a marker for neuroendocrine tumors, its role in cardiovascular disease states including essential hypertension (EH) has only recently been recognized. It acts as a prohormone giving rise to bioactive peptides such as vasostatin-I (human CHGA1–76) and catestatin (human CHGA352–372) that exhibit several cardiovascular regulatory functions. CHGA is over-expressed but catestatin is diminished in EH. Moreover, genetic variants in the promoter, catestatin, and 3′-untranslated regions of the human CHGA gene alter autonomic activity and blood pressure. Consistent with these findings, targeted ablation of this gene causes severe arterial hypertension and ventricular hypertrophy in mice. Transgenic expression of the human CHGA gene or exogenous administration of catestatin restores blood pressure in these mice. Thus, the accumulated evidence establishes CHGA as a novel susceptibility gene for EH.
30 citations
TL;DR: Molecular interactions between human CST peptides and human α3β4 nAChR are shown, and it is demonstrated that alterations in the CST secondary structure lead to the gain of potency for CST-370L and loss of potencyFor CST-364S, having implications for understanding the nicotinic cholinergic signaling in humans.
Abstract: Catestatin (CST), a chromogranin-A-derived peptide, is a potent endogenous inhibitor of the neuronal nicotinic acetylcholine receptor (nAChR). It exerts an anti-hypertensive effect by acting as a 'physiological brake' on transmitter release into the circulation. However, the mechanism of interaction of CST with nAChR is only partially understood. To unravel molecular interactions of the wild-type human CST (CST-WT) as well as its naturally occurring variants (CST-364S and CST-370L, which have Gly→Ser and Pro→Leu substitutions, respectively) with the human α3β4 nAChR, we generated a homology-modeled human α3β4 nAChR structure and solution structures of CST peptides. Docking and molecular dynamics simulations showed that ~90% of interacting residues were within 15 N-terminal residues of CST peptides. The rank order of binding affinity of these peptides with nAChR was: CST-370L>CST-WT>CST-364S; the extent of occlusion of the receptor pore by these peptides was also in the same order. In corroboration with computational predictions, circular dichroism analysis revealed significant differences in global structures of CST peptides (e.g. the order of α-helical content was: CST-370L>CST-WT>CST-364S). Consistently, CST peptides blocked various stages of nAChR signal transduction, such as nicotine- or acetylcholine-evoked inward current, rise in intracellular Ca(2+) and catecholamine secretion in or from neuron-differentiated PC12 cells, in the same rank order. Taken together, this study shows molecular interactions between human CST peptides and human α3β4 nAChR, and demonstrates that alterations in the CST secondary structure lead to the gain of potency for CST-370L and loss of potency for CST-364S. These findings have implications for understanding the nicotinic cholinergic signaling in humans.
27 citations
"Catestatin Gly364Ser Variant Alters..." refers background in this paper
...pathetic–chromaffin system because of its potent catecholamine release–inhibitory function,(12,13) which it manifests by acting specifically on the neuronal nicotinic acetylcholine receptor.(14,15)...
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TL;DR: Interestingly, the Ser-364 allele (detected in ∼15% subjects) was strongly associated with profound reduction in plasma norepinephrine/epinephrine levels consistent with the diminished nAChR desensitization-blocking effect of CST-Ser-364 as compared with CST-WT.
19 citations
"Catestatin Gly364Ser Variant Alters..." refers background or methods in this paper
...We also resequenced the CHGA promoter region in 581 study subjects using specific primers.(19)...
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...covered a novel SNP, Gly367Val (rs200576557), in a Chennai (South India) population.(19) In this report, we analyzed the effect...
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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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...The CST wild-type (CST-WT, SSMKLSFRARAYGFRGPGPQL) and CST-364Ser variant (CST-364Ser, SSMKLSFRARAYSFRGPGPQL) peptides were synthesized by solid-phase method and purified as described previously.(19)...
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