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Nitish R Mahapatra
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Nitish R Mahapatra
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Nitish R Mahapatra
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Mahapatra, N. R.
Mahapatra, Nitish R.
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13 results
Now showing 1 - 10 of 13
- PublicationChromogranin A: A novel susceptibility gene for essential hypertension(01-03-2010)
;Sahu, Bhavani S. ;Sonawane, Parshuram J.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. - PublicationMolecular interactions of the physiological anti-hypertensive peptide catestatin with the neuronal nicotinic acetylcholine receptor(01-06-2012)
;Sahu, Bhavani S. ;Mohan, Jagan ;Sahu, Giriraj ;Singh, Pradeep K. ;Sonawane, Parshuram J. ;Sasi, Binu K. ;Allu, Prasanna K.R. ;Maji, Samir K.; ; - PublicationFunctional Gly297Ser Variant of the Physiological Dysglycemic Peptide Pancreastatin Is a Novel Risk Factor for Cardiometabolic Disorders(01-03-2022)
;Allu, Prasanna K.R. ;Kiranmayi, Malapaka ;Mukherjee, Sromona D. ;Chirasani, Venkat R. ;Garg, Richa ;Vishnuprabu, Durairajpandian ;Ravi, Sudesh ;Subramanian, Lakshmi ;Sahu, Bhavani S. ;Iyer, Dhanya R. ;Maghajothi, Sakthisree ;Sharma, Saurabh ;Ravi, Marimuthu S. ;Khullar, Madhu ;Munirajan, Arasambattu K. ;Gayen, Jiaur R.; ;Mullasari, Ajit S. ;Mohan, Viswanathan ;Radha, Venkatesan ;Naga Prasad, Sathyamangala V.Pancreastatin (PST), a chromogranin A–derived potent physiological dysglycemic peptide, regulates glucose/insu-lin homeostasis. We have identified a nonsynonymous functional PST variant (p.Gly297Ser; rs9658664) that occurs in a large section of human populations. Association analysis of this single nucleotide polymorphism with cardiovas-cular/metabolic disease states in Indian populations (n 5 ~4,300 subjects) displays elevated plasma glucose, glyco-sylated hemoglobin, diastolic blood pressure, and cate-cholamines in Gly/Ser subjects as compared with wild-type individuals (Gly/Gly). Consistently, the 297Ser allele confers an increased risk (~1.3–1.6-fold) for type 2 diabe-tes/hypertension/coronary artery disease/metabolic syn-drome. In corroboration, the variant peptide (PST-297S) displays gain-of-potency in several cellular events relevant for cardiometabolic disorders (e.g., increased expression of gluconeogenic genes, increased catecholamine secre-tion, and greater inhibition of insulin-stimulated glucose uptake) than the wild-type peptide. Computational docking analysis and molecular dynamics simulations show higher affinity binding of PST-297S peptide with glucose-regu-lated protein 78 (GRP78) and insulin receptor than the wild-type peptide, providing a mechanistic basis for the enhanced activity of the variant peptide. In vitro binding assays validate these in silico predictions of PST peptides binding to GRP78 and insulin receptor. In conclusion, the PST 297Ser allele influences cardiovascular/metabolic phenotypes and emerges as a novel risk factor for type 2 diabetes/hypertension/coronary artery disease in human populations. - PublicationFunctional genetic variants of the catecholamine-release-inhibitory peptide catestatin in an Indian population: Allele-specific effects on metabolic traits(21-12-2012)
;Sahu, Bhavani S. ;Obbineni, Jagan M. ;Sahu, Giriraj ;Allu, Prasanna K.R. ;Subramanian, Lakshmi ;Sonawane, Parshuram J. ;Singh, Pradeep K. ;Sasi, Binu K.; ;Maji, Samir K.; ;Gomathi, Balashankar S. ;Mullasari, Ajit S.Catestatin (CST), a chromogranin A (CHGA)-derived peptide, is a potent inhibitor of catecholamine release from adrenal chromaffin cells and postganglionic sympathetic axons. We resequenced the CST region of CHGA in an Indian population (n = 1010) and detected two amino acid substitution variants: G364S and G367V. Synthesized CST variant peptides (viz. CST-Ser-364 and CST-Val-367) were significantly less potent than the wild type peptide (CST-WT) to inhibit nicotine-stimulated catecholamine secretion from PC12 cells. Consistently, the rank-order of blockade of nicotinic acetylcholine receptor (nAChR)-stimulated inward current and intracellular Ca2+ rise by these peptides in PC12 cells was: CST-WT > CST-Ser-364 > CST-Val-367. Structural analysis by CD spectroscopy coupled with molecular dynamics simulations revealed the following order of α-helical content: CST-WT > CST-Ser-364 > CST-Val-367; docking of CST peptides onto a major human nAChR subtype and molecular dynamics simulations also predicted the above rank order for their binding affinity with nAChR and the extent of occlusion of the receptor pore, providing a mechanistic basis for differential potencies. The G364S polymorphism was in strong linkage disequilibrium with several common CHGA genetic variations. Interestingly, the Ser-364 allele (detected in ∼15% subjects) was strongly associated with profound reduction (up to ∼2.1-fold) in plasma norepinephrine/epinephrine levels consistent with the diminished nAChR desensitization-blocking effect of CST-Ser-364 as compared with CST-WT. Additionally, the Ser-364 allele showed strong associations with elevated levels of plasma triglyceride and glucose levels. In conclusion, a common CHGA variant in an Indian population influences several biochemical parameters relevant to cardiovascular/metabolic disorders. © 2012 by The American Society for Biochemistry and Molecular Biology, Inc. - PublicationCoordinated transcriptional regulation of hspa1a gene by multiple transcription factors: Crucial roles for HSF-1, NF-Y, NF-κB, and CREB(09-01-2014)
;Sasi, Binu K. ;Sonawane, Parshuram J. ;Gupta, Vinayak ;Sahu, Bhavani S.Although the transcript level of inducible heat shock protein 70.3 (Hsp70.3, also known as Hspa1a) is altered in various disease states, its transcriptional regulation remains incompletely understood. Here, we systematically analyzed the Hspa1a promoter to identify major cis elements and transcription factors that may govern the constitutive/inducible gene expression. Computational analyses coupled with extensive in vitro (promoter-reporter activity and electrophoretic mobility shift assays) and in vivo (chromatin immunoprecipitation assays) revealed interaction of several transcription factors with Hspa1a promoter motifs: HSF-1 (heat shock factor 1) at - 114/- 97 bp and - 788/- 777 bp, NF-Y (nuclear transcription factor Y) at - 73/- 58 bp, NF-κB (nuclear factor kappa B) at - 133/- 124 bp, and CREB (cAMP response element binding protein) at - 483/- 476 bp. Consistently, siRNA (small interfering RNA)-mediated down-regulation of each of these transcription factors caused substantial reduction of endogenous Hspa1a expression. Heat-shock-induced activation of Hspa1a was coordinately regulated by HSF-1 and NF-Y/NF-κB. The Hspa1a expression was augmented by TNF-α (tumor necrosis factor-alpha) and forskolin in NF-κB and CREB-dependent manners, respectively. NF-κB and CREB also activated Hspa1a transcription in cardiac myoblasts upon exposure to ischemia-like conditions. Taken together, this study discovered previously unknown roles for NF-κB and CREB to regulate Hspa1a expression and a coordinated action by several transcription factors for Hspa1a transactivation under heat-shock/ischemia-like conditions and thereby provided new insights into the mechanism of Hspa1a regulation. © 2013 Elsevier Ltd. - PublicationIdentification and Functional Characterization of Genetic Variants of the Catecholamine Release-Inhibitory Peptide Catestatin in an Indian Population(01-01-2013)
;Sahu, Bhavani S. ;Subramanian, Lakshmi ;Allu, Prasanna K.R. ;Sahu, Giriraj ;Mohan, Jagan ;Singh, Pradeep K. ;Gomathi, Balashankar ;Maji, Samir K.; ; ;Mullasari, Ajit S. - PublicationTranscriptional regulation of the novel monoamine oxidase renalase: Crucial roles of transcription factors Sp1, STAT3, and ZBP89(11-11-2014)
;Sonawane, Parshuram J. ;Gupta, Vinayak ;Sasi, Binu K. ;Kalyani, Ananthamohan ;Natarajan, Bhargavi ;Khan, Abrar A. ;Sahu, Bhavani S.Renalase, a novel monoamine oxidase, is emerging as an important regulator of cardiovascular, metabolic, and renal diseases. However, the mechanism of transcriptional regulation of this enzyme remains largely unknown. We undertook a systematic analysis of the renalase gene to identify regulatory promoter elements and transcription factors. Computational analysis coupled with transfection of human renalase promoter/luciferase reporter plasmids (5′-promoter-deletion constructs) into various cell types (HEK-293, IMR32, and HepG2) identified two crucial promoter domains at base pairs -485 to -399 and -252 to -150. Electrophoretic mobility shift assays using renalase promoter oligonucleotides with and without potential binding sites for transcription factors Sp1, STAT3, and ZBP89 displayed formation of specific complexes with HEK-293 nuclear proteins. Consistently, overexpression of Sp1, STAT3, and ZBP89 augmented renalase promoter activity; additionally, siRNA-mediated downregulation of Sp1, STAT3, and ZBP89 reduced the level of endogenous renalase transcription as well as the transfected renalase promoter activity. In addition, chromatin immunoprecipitation assays showed in vivo interactions of these transcription factors with renalase promoter. Interestingly, renalase promoter activity was augmented by nicotine and catecholamines; while Sp1 and STAT3 synergistically activated the nicotine-induced effect, Sp1 appeared to enhance epinephrine-evoked renalase transcription. Moreover, renalase transcript levels in mouse models of human essential hypertension were concomitantly associated with endogenous STAT3 and ZBP89 levels, suggesting crucial roles for these transcription factors in regulating renalase gene expression in cardiovascular pathological conditions. - PublicationA haplotype variant of the human chromogranin A gene (CHGA) promoter increases CHGA expression and the risk for cardiometabolic disorders(25-08-2017)
;Subramanian, Lakshmi ;Khan, Abrar A. ;Allu, Prasanna K.R. ;Kiranmayi, Malapaka ;Sahu, Bhavani S. ;Sharma, Saurabh ;Khullar, Madhu ;Mullasari, Ajit S.The acidic glycoprotein chromogranin A (CHGA) is co-stored/co-secreted with catecholamines and crucial for secretory vesicle biogenesis in neuronal/neuroendocrine cells. CHGA is dysregulated in several cardiovascular diseases, but the underlying mechanisms are not well established. Here, we sought to identify common polymorphisms in the CHGA promoter and to explore the mechanistic basis of their plausible contribution to regulating CHGA protein levels in circulation. Resequencing of the CHGA promoter in an Indian population (n=769) yielded nine single-nucleotide polymorphisms (SNPs): G-1106A, A-1018T, T-1014C, T-988G,G-513A,G-462A, T-415C, C-89A, and C-57T. Linkage disequilibrium (LD) analysis indicated strong LD among SNPs at the -1014, -988, -462, and -89 bp positions and between the -1018 and -57 bp positions. Haplotype analysis predicted five major promoter haplotypes that displayed differential promoter activities in neuronal cells; specifically, haplotype 2 (containing variant T alleles at -1018 and -57 bp) exhibited the highest promoter activity. Systematic computational and experimental analyses revealed that transcription factor c-Rel has a role in activating the CHGA promoter haplotype 2 under basal and pathophysiological conditions(viz. inflammation and hypoxia). Consistent with the higher in vitro CHGA promoter activity of haplotype 2, individuals carrying this haplotype had higher plasma CHGA levels,plasma glucose levels, diastolic blood pressure, and body mass index. In conclusion, these results suggest a functional role of the CHGA promoter haplotype 2 (occurring in a large proportionof the world population) in enhancing CHGA expression in haplotype 2 carriers who may be at higher risk for cardiovascular/metabolic disorders. - PublicationCorrigendum to “Coordinated Transcriptional Regulation of Hspa1a Gene by Multiple Transcription Factors: Crucial Roles for HSF-1, NF-Y, NF-κB, and CREB†(Coordinated Transcriptional Regulation of Hspa1a Gene by Multiple Transcription Factors: Crucial Roles for HSF-1, NF-Y, NF-κB, and CREB (2014) 426(1) (116–135), (S0022283613005779), (10.1016/j.jmb.2013.09.008))(03-05-2019)
;Sasi, Binu K. ;Sonawane, Parshuram J. ;Gupta, Vinayak ;Sahu, Bhavani S.The authors regret typing errors on page 132 in the DNA sequence of mHsp-2686-RT-RP primer in the second sentence of the subsection entitled “Extraction of RNA and real-time PCR” under the Materials and Methods section of the article. The sentence should be read as follows: Real-time PCR was carried out using the DyNAmo™ HS SYBR® Green qPCR kit (Finnzymes, USA) and mHspa1a gene-specific primers (forward, mHsp-2406-RT-FP: 5′-TGCCCCGCTGATGTGATTTG-3′ and reverse, mHsp-2686-RT-RP: 5′-CACCAACCTGGAAACAAGTCCTAC-3′). The authors would like to apologize for any inconvenience caused. - PublicationCatestatin Gly364Ser Variant Alters Systemic Blood Pressure and the Risk for Hypertension in Human Populations via Endothelial Nitric Oxide Pathway(01-08-2016)
;Kiranmayi, Malapaka ;Chirasani, Venkat R. ;Allu, Prasanna K.R. ;Subramanian, Lakshmi ;Martelli, Elizabeth E. ;Sahu, Bhavani S. ;Vishnuprabu, Durairajpandian ;Kumaragurubaran, Rathnakumar ;Sharma, Saurabh ;Bodhini, Dhanasekaran; ;Munirajan, Arasambattu K. ;Khullar, Madhu ;Radha, Venkatesan ;Mohan, Viswanathan ;Mullasari, Ajit S. ;Prasad, Sathyamangla V.Naga; 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.