Nitish R Mahapatra

• Ph.D., Indian Institute of Chemical Biology
• Professor at Indian Institute of Technology Madras

Catestatin (CST), a 21-amino acids physiological peptide, has emerged as a key modulator of cardiovascular functions due to its anti-hypertensive and cardioprotective properties. However, the ramifications of the most common human variant of CST (viz. Gly364Ser) on cardiovascular pathophysiology remain partially understood. In this study, hypertens...

Biomedical engineering strives for innovation to enhance the safety and effectiveness of medical tools, such as catheters and stents that need to be operated in confined spaces, with precise drug delivery control and should possess anti-fouling properties. Soft actuators with superhydrophobic surfaces can provide adaptable shape change together wit...

Photothermal nanoparticle-sensitised photoporation is an emerging approach, which is considered an efficient tool for the intracellular delivery of biomolecules. Nevertheless, using this method to achieve high transfection efficiency generally compromises cell viability and uneven distribution of nanoparticles results in non-uniform delivery. Here,...

The Descemet Membrane Endothelial Keratoplasty (DMEK) procedure for corneal transplantation is challenging due to the need to unscroll the donor graft within the recipient's eye. This process of unscrolling is complex, time-consuming, leads to a loss of endothelial cells and, most importantly, can negatively impact the graft's adhesion and integrat...

Chromogranin A (CHGA), a member of the granin family of proteins, has been an attractive therapeutic target and candidate biomarker for several cardiovascular, neurological, and inflammatory disorders. The prominence of CHGA stems from the pleiotropic roles of several bioactive peptides (e.g., catestatin, pancreastatin, vasostatins) generated by it...

Aims: Renalase, a key mediator of cross-talk between kidneys and sympathetic nervous system, exerts protective roles in various cardiovascular/renal disease states. However, molecular mechanisms underpinning renalase gene expression remain incompletely understood. Here, we sought to identify the key molecular regulators of renalase under basal/cat...

Background: Diabetic cardiomyopathy (DCM) is a leading cause of death in diabetic patients. Hyperglycemic myocardial microenvironment significantly alters chromatin architecture and the transcriptome, resulting in aberrant activation of signaling pathways in a diabetic heart. Epigenetic marks play vital roles in transcriptional reprogramming durin...

Uniform transfection of biomolecules into live cells with high delivery efficiency and cell viability is an immensely important area of biological research and has many biomedical applications. In the present study, we report highly efficient, uniform parallel intracellular delivery of small to very large biomolecules into diverse cell types using...

Uniform transfection of biomolecules into live cells with high delivery efficiency and cell viability is an immensely important area of biological research and has many biomedical applications. In the present study, we report highly efficient, uniform parallel intracellular delivery of small to very large biomolecules into diverse cell types using...

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causing corona virus disease 2019 (COVID-19) can infect multiple tissues, including endocrine organs, such as the pancreas, adrenal, thyroid, and adipose tissue. The main receptor for SARS-CoV-2, ACE2, is ubiquitously expressed in the cells of the endocrine organs and accordingly, the...

Peroxiredoxin-3 (Prx-3), a thioredoxin-dependent peroxidase located exclusively in the mitochondrial matrix, catalyses peroxides/peroxinitrites. Altered levels of Prx-3 is associated with diabetic cardiomyopathy (DCM). However, molecular mechanisms of Prx-3 gene regulation remain partially understood. We undertook a systemic analysis of the Prx-3 g...

Heat Shock Proteins (HSPs) are evolutionarily conserved proteins from prokaryotes to eukaryotes. They are ubiquitous proteins involved in key physiological and cellular pathways (viz. inflammation, immunity and apoptosis). Indeed, the survivability of the cells under various stressful conditions depends on appropriate levels of HSP expression. Ther...

Hydrogel-based pH-responsive bilayer actuators exhibit bidirectional actuation due to the differences in the concentration gradient developed across the thickness, the volume expansion due to swelling, and the mechanical stiffness of the layers involved. At a pH value (point), where the sum of these factors generates moments of equal magnitudes, th...

Renalase is a ~38 kDa flavin-adenine dinucleotide (FAD) domain-containing protein that can function as a cytokine and an anomerase. It is emerging as a novel regulator of cardiometabolic diseases. Expressed mainly in the kidneys, renalase has been reported to have a hypotensive effect and may control blood pressure through regulation of sympathetic...

Objectives: Matrix metalloproteinase 8 (MMP8) has a prominent role in collagen turnover in blood vessels and vascular remodeling. The contribution of regulatory single nucleotide polymorphisms in MMP8 to cardiovascular diseases is unclear. We aimed to delineate the influence of MMP8 promoter variations on hypertension. Methods: A case-control st...

Dysregulation of lipid metabolism is associated with cardiovascular/metabolic diseases, including atherosclerosis, liver diseases and type 2 diabetes mellitus (T2DM). Several miRNAs have been reported as regulators of different stages of lipid homeostasis, including cholesterol/fatty acid biosynthesis, degradation, transport, storage, and low-densi...

Pancreastatin (PST), a chromogranin A (CHGA)-derived potent physiological dysglycemic peptide, regulates glucose/insulin homeostasis. We have identified a non-synonymous functional PST variant (p.Gly297Ser; rs9658664) that occurs in a large section of human populations. Association analysis of this single nucleotide polymorphism with cardiovascular...

3-Hydroxy-3-methyl glutaryl-coenzyme A reductase (Hmgcr) encodes the rate-limiting enzyme in the cholesterol biosynthesis pathway. The regulation of Hmgcr in rat models of genetic hypertension (viz. Spontaneously Hypertensive Rats [SHR] and its normotensive control Wistar/Kyoto [WKY] strain) is unclear. Interestingly, Hmgcr transcript and protein l...

Kidneys have a high resting metabolic rate and low partial pressure of oxygen due to enhanced mitochondrial oxygen consumption and ATP production needed for active solute transport. Heightened mitochondrial activity leads to progressively increasing hypoxia from the renal cortex to the renal medulla. Renal hypoxia is prominent in hypertensive rats...

Hypercholesterolemia is a strong predictor of cardiovascular diseases. 3-Hydroxy-3-methylglutaryl-coenzyme A reductase gene ( Hmgcr ) coding for the rate-limiting enzyme in the cholesterol biosynthesis pathway is a crucial regulator of plasma cholesterol levels. However, the post-transcriptional regulation of Hmgcr remains poorly understood. The ma...

Catestatin (CST) is a catecholamine release-inhibitory peptide secreted from the adrenergic neurons and the adrenal glands. It regulates the cardiovascular functions and it is associated with cardiovascular diseases. Though its mechanisms of actions are not known, there are evidences of cross-talk between the adrenergic and CST signaling. We hypoth...

Catestatin (CST) is a catecholamine release-inhibitory peptide secreted from the adrenergic neurons and the adrenal glands. It regulates the cardiovascular functions and it is associated with cardiovascular diseases. Though its mechanisms of actions are not known, there are evidences of cross-talk between the adrenergic and CST signaling. We hypoth...

Monoamine oxidases (MAOs) are flavoenzymes that metabolize biogenic amines, dietary amines, and catecholamines in the brain and peripheral tissues. While MAOs are known to contribute to psychiatric and neurodegenerative (Parkinson’s and Alzheimer’s) diseases for a long time, recent studies have established their role in heart diseases as these enzy...

MMP (matrix metalloproteinase)-7-a potent extracellular matrix degrading enzyme-is emerging as a new regulator of cardiovascular diseases. However, potential contributions of MMP7 genetic variations to hypertension remain unknown. In this study, we probed for the association of a tag single-nucleotide polymorphism in the MMP7 promoter (-181A/G; rs1...

Introduction: Kidneys are organs with high resting metabolic rate and low tissue pO2 due to enhanced mitochondrial oxygen consumption and ATP production for active solute transport. Such enhanced mitochondrial activity leads to progressive hypoxia from the renal cortex to medulla. Renal tubulointerstitial hypoxia (TiH) is severe in hypertensive rat...

3-Hydroxy-3-methyl glutaryl-coenzyme A reductase (Hmgcr) encoding the rate-limiting enzyme in the cholesterol biosynthesis pathway is a candidate gene for essential hypertension (EH). However, the regulation of Hmgcr in rat models of hypertension (viz. Spontaneously Hypertensive Rats [SHR] and its normotensive control Wistar/Kyoto [WKY] strain) is...

MMP7 (Matrilysin), a potent extracellular matrix degrading enzyme with wide substrate specificity, is emerging as a new regulator of cardiovascular diseases including coronary artery disease and atherosclerosis. However, potential contributions of MMP7 genetic variations to hypertension remain unknown. In this study, we first probed for the associa...

Monoamine oxidase B (MAO-B), a flavoenzyme located in the outer mitochondrial membrane, is involved in the catabolism of monoamines. Altered levels of MAO-B are associated with cardiovascular/neuronal diseases. However, molecular mechanisms of MAO-B gene regulation are partially understood. We undertook a systematic analysis of the MAO-B gene to id...

Hypercholesterolemia is a strong predictor of cardiovascular diseases. 3-Hydroxy-3-methylglutaryl-coenzyme A reductase gene ( Hmgcr ) coding for the rate-limiting enzyme in the cholesterol biosynthesis pathway is a crucial regulator of plasma cholesterol levels. However, the post-transcriptional regulation of Hmgcr remains poorly understood. The ma...

Antagonistic bacteria arecommon soilinhabitants withpotential tocontrol several soil-borne diseases ofvarious crops. In this study, two methomyl degrading Bacillus sp. were screened for their antagonistic potential against soilbornepathogen identifiedas Alternariasp. whichcauses leafspot andblightdiseaseinlentil. Boththe strains produced non-volatil...

Single nucleotide polymorphisms (SNPs) refer to changes of a single DNA base, which accounts for ~90% of human sequence variations. Chromogranin A (CgA) is a secretory protein whose plasma concentration is augmented in established essential (hereditary) hypertension, in heart failure patients and in patients with renal failure. Resequencing of CHGA...

The acidic glycoprotein chromogranin A (CHGA) is co-stored/co-secreted with catecholamines and crucial for secretory vesicles 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 promo...

Chromogranin A (CgA) is a prohormone and a granulogenic factor that regulates secretory pathways in neuroendocrine tissues. In β-cells of the endocrine pancreas, CgA is a major cargo in insulin secretory vesicles. The impact of CgA deficiency on the formation and exocytosis of insulin vesicles is yet to be investigated. In addition, no literature e...

Background: Cardiovascular disease (CVD), the most common cause of death globally, accounts for ~30% of all deaths worldwide. Hypertension is a common contributor to morbidity and mortality from CVD. Methods and results: The plasma concentration of chromogranin A (CgA) is elevated in patients with CVD as well as patients with established human e...

Despite the well-known role of cystathionine γ-lyase (Cth) in cardiovascular pathophysiology, transcriptional regulation of Cth remains incompletely understood. Sequencing of the Cth promoter region in mouse models of genetic/essential hypertension (viz. Blood Pressure High [BPH], Blood Pressure Low [BPL] and Blood Pressure Normal [BPN] mice) ident...

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-...

Chromogranin A (CHGA) is a major protein in the secretory granules of chromaffin cells. CHGA also gives rise to cardiovascular/metabolism regulatory peptides, such as catestatin (CST) and pancreastatin (PST). While CST is a potent inhibitor of catecholamine secretion, PST is a potent physiological inhibitor of glucose-induced insulin secretion. Rec...

The KIF6 719Arg allele is an interesting genomic variant widely screened in various populations and is reported to be associated with the risk of Coronary Artery Disease (CAD) and statin treatment outcome. Recent population based clinical studies and large-scale meta-analyses pondered over the role of 719Arg variant in CAD risk and treatment respon...

Elevated expression of matrix metalloproteinase7 (MMP7) has been demonstrated to play a pivotal role in cancer invasion. The -181A/G (rs11568818) polymorphism in MMP7 promoter modulates gene expression and plausibly affects cancer progression. Here, we evaluated the impact of -181A/G polymorphism in MMP7 promoter activity and its association with g...

Monoamine oxidase A (MAOA) plays important roles in the pathogenesis of several neurological and cardiovascular disorders. The mechanism of transcriptional regulation of MAOA under basal and pathological conditions, however, remains incompletely understood. Here, we report systematic identification and characterization of cis elements and transcrip...

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. Computati...

Pancreastatin (PST), a chromogranin A-derived peptide, is a potent physiological inhibitor of glucose-induced insulin secretion. PST also triggers glycogenolysis in liver and reduces glucose uptake in adipocytes and hepatocytes. Here, we probed for genetic variations in PST sequence and identified two variants within its functionally important carb...

PS3-P77 Common single nucleotide polymorphisms in the chromogranin A gene alter the risk for cardiometabolic syndrome Background: Chromogranin A (CHGA), ubiquitously expressed in secretory cells of the neuroendocrine system, plays a key role for vesicle biogenesis and cleaves to bioactive peptides including catecholamine-release-inhibitory “catesta...

High consumer preference together with its polyculture potential has undoubtedly driven Rohu (Labeo rohita) and Catla (Catla catla) to top the list of the most preferred fishes among the Indian major carps. Commonly found in these fishes are hybrids that can be natural or man-made. Increasing emphasis on biodiversity issues has necessitated proper...

Hypertension is a common hereditary syndrome with unclear pathogenesis. Chromogranin A (Chga), which catalyzes formation and cargo storage of regulated secretory granules in neuroendocrine cells, contributes to blood pressure homeostasis centrally and peripherally. Elevated Chga occurs in Spontaneously Hypertensive Rat (SHR) adrenal glands and plas...

Catestatin (CST), a chromogranin A (CHGA)-derived peptide, is a potent inhibitor of catecholamine release from adrenal chromaffin cells and postganglionic sympathetic axons. We re-sequenced 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 (...

Essential hypertension, a common complex disease, displays substantial genetic influence. Contemporary methods to dissect the genetic basis of complex diseases such as the genomewide association study are powerful, yet a large gap exists between the fraction of population trait variance explained by such associations and total disease heritability....

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. T...

Pituitary adenylyl cyclase activating polypeptide (PACAP) and vasoactive intestinal polypeptide (VIP) augment the biosynthesis of tyrosine hydroxylase (TH). We tested whether secretin belonging to the glucagon/PACAP/VIP superfamily would increase transcription of the tyrosine hydroxylase (Th) gene and modulate catecholamine secretion. Secretin acti...

Basal expression of Hmgcr promoter-luciferase reporter plasmids in cultured cells. (DOC)

Supplementary methods. (DOC)

3-Hydroxy-3-methylglutaryl-coenzyme A [HMG-CoA] reductase gene (Hmgcr) is a susceptibility gene for essential hypertension. Sequencing of the Hmgcr locus in genetically hypertensive BPH (blood pressure high), genetically hypotensive BPL (blood pressure low) and genetically normotensive BPN (blood pressure normal) mice yielded a number of single nuc...

Improvement of the specificity and efficiency of the polymerase chain reaction (PCR) by nanoparticles is an emerging area of research. We observed that TiO(2) nanoparticles of approximately 25 nm diameter caused significant enhancement of PCR efficiency for various types of templates (namely plasmid DNA, genomic DNA and complementary DNA). By a ser...

Understanding catecholamine metabolism is crucial for elucidating the pathogenesis of hereditary hypertension. Here we integrated transcriptional and biochemical profiling with physiologic quantitative trait locus (eQTL and pQTL) mapping in adrenal glands of the HXB/BXH recombinant inbred (RI) strains, derived from the spontaneously hypertensive ra...

Chromogranin A (CHGA) has a crucial role in formation of regulated secretory granules in neuroendocrine tissues and is also a prohormone that is proteolytically processed into peptides with diverse and complex actions. CHGA and several of its peptide products, including catestatin and pancreastatin, are implicated in pathogenesis of essential hyper...

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...

Chromogranin A (CHGA) is stored and released from the same secretory vesicles that contain catecholamines in chromaffin cells and noradrenergic neurons. We had previously identified common genetic variants at the CHGA locus in several human populations. Here we focus on whether inter-individual variants in the promoter region are of physiological s...

Secretion of proteins and peptides from eukaryotic cells takes place by both constitutive and regulated pathways. Regulated secretion may involve interplay of proteins that are currently unknown. Recent studies suggest an important role of chromogranin A (CHGA) in the regulated secretory pathway in neuroendocrine cells, but the mechanism by which C...

Catestatin is a 21-amino acid residue, cationic and hydrophobic peptide that is formed endogenously by proteolytic cleavage of its precursor chromogranin A, a major protein co-stored and co-released with catecholamines from the storage vesicles in adrenal chromaffin cells and adrenergic neurons. This peptide exhibits potent catecholamine release-in...

An Acidiphilium cryptum strain and two Acidiphilium symbioticum strains exhibited extremely high tolerance to CdSO4, growing at a concentration of 700 mmol l-1 or more in MGY medium (g l-1 composition: KCl, 0.1; MgSO4.7H2O, 0.25; (NH4)2SO4, 2.0; K2HPO4, 0.25; glucose, 1.0; yeast extract, 0.1) of pH 3. Fairly high concentrations of ZnSO4 (200 > 125...

Renal organic anion transporters (OAT) are known to mediate the excretion of many drugs, but their function in normal physiology is not well understood. In this study, mice lacking organic anion transporter 3 (Oat3) had a 10 to 15% lower BP than wild-type mice, raising the possibility that Oat3 transports an endogenous regulator of BP. The aldoster...

Chromogranins or secretogranins (granins), present in secretory granules of virtually all neuroendocrine cells and neurones, are structurally related proteins encoded by different genetic loci: chromogranins A and B, and secretogranins II through VI. Compelling evidence supports both intracellular and extracellular functions for this protein family...

The molecular basis of neuroendocrine-specific expression of chromogranin B gene (Chgb) has remained elusive. Utilizing wild-type and mutant Chgb promoter/luciferase reporter constructs, this study established a crucial role for the cAMP response element (CRE) box at -102/-95 bp in endocrine [rat pheochromocytoma (chromaffin) cell line (PC12) and r...

Secretory granules of chromaffin cells and neurons co-store and release, by exocytosis, the acidic soluble protein chromogranin A (human, CHGA; rodent, Chga) along with catecholamines, neuropeptides and adenosine triphosphate (ATP). CHGA serves as a pro-protein and upon proteolytic cleavage it generates active peptides, including catestatin (human...

Family studies have suggested a genetic contribution to variation in blood pressure, but the genes responsible have thus far eluded identification. The use of intermediate phenotypes associated with hypertension, such as chromogranin plasma concentrations, may assist the discovery of hypertension-predisposing loci. We measured the concentrations of...

The chromogranin/secretogranins (Cg/Sg) are a family of soluble, acidic proteins representing major constituents in secretory vesicle cores of virtually all neuroendocrine tissues. We and others have identified the cyclic adenosine monophosphate response element (CRE) as the crucial promoter element responsible for neuroendocrine cell type-specific...

The secretory prohormone chromogranin A (CHGA) is overexpressed in essential hypertension, a complex trait with genetic predisposition, while its catecholamine release-inhibitory fragment catestatin is diminished, and low catestatin predicts augmented adrenergic pressor responses. These findings from studies on humans suggest a mechanism whereby di...

Genetic studies of essential hypertension, a complex, polygenic, and age-dependent disorder, have not been able to completely elucidate the genes responsible for development of the trait. We used a novel strategy to compare gene expression in the adrenal gland of two independent rodent models of human essential hypertension (the spontaneously hyper...

Resequencing of the human chromogranin A gene identified three human variants of catestatin: Gly364Ser, Pro370Leu, and Arg374Gln. Naturally occurring variants were tested for ability to inhibit four nicotinic processes. The rank order of potency for inhibition of catecholamine secretion was Pro370Leu> wild type> Gly364Ser> Arg374Gln. Decrease in po...

Acidophilic bacteria of mine origin are ideal systems for studying microbial metal resistance because of their ability to grow in the presence of high concentrations of metal salts. We have previously shown that the metal-resistant transformants obtained after transformation of Escherichia coli DH5alpha with plasmid DNA preparation from Acidocella...

Chromaffin vesicles contain very high concentration of Ca2+ (∼20-40 mM total), compared with ∼100 nM in the cytosol. Aequorin, a jellyfish photoprotein with Ca2+-dependent luminescence, measures [Ca2+] in specific subcellular compartments wherein proteins with organelle-specific trafficking domains are fused in-frame to aequorin. Because of the pre...

The catestatin fragment of chromogranin A is an endogenous inhibitor of nicotinic cholinergic transmission, functioning in negative feedback control of catecholamine secretion. We explored naturally occurring polymorphisms in the amino acid sequence of catestatin. Three human variants were identified: Gly364Ser, Pro370Leu, and Arg374Gln. Variants w...

The genetic basis of hypertension in the genetically/hereditary hypertensive (BPH/2) mouse strain is incompletely understood, although a recent genome scan uncovered evidence for several susceptibility loci. To probe the neuroendocrine transcriptome in this disease model, 12 488 probe set microarray experiments were performed on mRNA transcripts fr...

Previous modeling (PDB 1cfk) of the catecholamine release-inhibitory "catestatin" region of chromogranin A (CgA) suggested a beta-strand/loop/beta-strand active conformation, displaying an electropositive Arg-rich loop (R(351)AR(353)GYGFR(358)). To explore this possibility, we studied NMR structures of linear and cyclic synthetic catestatin, bovine...