Molecular Genetics of Cardiovascular Diseases.
Cardiovascular diseases (coronary heart disease, heart failure, stroke etc.) affect a large section of the adult population and are the leading causes of morbidity and mortality in many countries including India. Recent studies have documented that although the mortality associated with cardiovascular diseases are declining in the developed countries including Western Europe and North America, the burden of cardiovascular diseases continues to rise in the developing countries including India. Notably, South Asians have a greater prevalence of cardiovascular risk factors than the rest of the World, and India itself is estimated to have more than half of the World’s heart disease patients at present. These diseases not only cause enormous loss of human lives, but also lead to huge health care cost, tremendous economic and social burden, declining national productivity and quality of life.
The determinants of cardiovascular diseases are multi-factorial, complex and often interrelated. We are interested to understand the molecular and genetic bases of hypertension (elevated arterial blood pressure) because it is the chief risk factor for cardiovascular diseases. Despite extensive research over the past couple of decades, the pathogenesis of hypertension is only partially understood. Besides environmental factors (such as stress, inadequate physical activity, smoking/tobacco use and unhealthy diet that includes higher dietary fats/higher sodium/lower fruits and vegetables), strong influences of genes have been reported. Moreover, hypertension may be associated with and complicated by dyslipidemia (elevated levels of LDL-cholesterol and triglycerides and reduced level of HDL-cholesterol in the circulation), a major risk factor for cardiovascular diseases. In addition, diabetes mellitus is another major risk factor for cardiovascular diseases. Indeed, more than 65% of people with diabetes mellitus die of some form of heart disease/stroke and heart disease death rates in adults with diabetes are at least two times higher as compared to those without diabetes. Therefore, we are also interested to unravel the genetic and molecular mechanisms that govern the pathogenesis of lipid disorder and type 2 diabetes.
Our experimental approach involves identification, transcriptional and post-transcriptional regulation of the candidate/susceptibility genes for hypertension and related cardiovascular disease states. We also study the roles of translated protein products of the candidate genes in disease pathogenesis. Additionally, we work on discovering naturally-occurring functional genetic variants (single nucleotide polymorphisms and haplotypes) that may act as risk factors for development of cardiovascular diseases. We investigate at the cellular level (employing cultured cell lines), utilize animal models (genetically modified rodents) and human subjects (cases versus controls) for our various studies. Results from these studies are likely to shed light on the molecular mechanisms and ultimately help to develop diagnostic and therapeutic strategies for management of the cardiovascular diseases.
I. Journal Articles.
50. Subramanian L, Khan AA, Allu PKR, Kiranmayi M, Sahu BS, Sharma S, Khullar M, Mullasari AS, Mahapatra NR. 2017. A haplotype variant of the human chromogranin A gene (CHGA) promoter increases CHGA expression and the risk for cardiometabolic disorders. J Biol Chem 292:13970-13985. (Featured in the following news media: http://www.thehindu.com/sci-tech/health/blame-it-on-the-genes/article19778751.ece; http://vigyanprasar.gov.in/isw/heartdisease.html; https://scroll.in/pulse/852266/lab-notes-scientists-identify-a-gene-that-puts-indians-at-higher-risk-of-heart-disease; https://biotechtimes.org/2017/09/28/scientists-discover-genetic-link/; http://www.apnlive.com/science/study-identifies-genetic-link-to-heart-disease-in-indian-population-28428; http://www.downtoearth.org.in/news/carrying-set-of-genes-puts-you-on-higher-risk-of-cardiovascular-diseases-study-58765; http://www.biovoicenews.com/study-identifies-genetic-link-heart-disease-indian-population/; http://netindian.in/news/2017/09/29/00043430/study-identifies-genetic-link-heart-disease-indian-population).
49. Mahata SK, Kiranmayi M, Mahapatra NR. 2017. Catestatin: A master regulator of cardiovascular functions. Curr Med Chem (doi:10.2174/0929867324666170425100416). [Epub ahead of print] PMID:28443506.
48. Wollam J, Mahata S, Riopel M, Hernandez-Carretero A, Biswas A, Bandyopadhyay GK, Chi NW, Eiden LE, Mahapatra NR, Corti A, Webster NJG, Mahata SK. 2017. Chromogranin A regulates vesicle storage and mitochondrial dynamics to influence insulin secretion. Cell Tissue Res 368:487-501.
47. Gupta V, Kapopara PR, Khan AA, Arige V, Subramanian L, Sonawane PJ, Sasi BK, Mahapatra NR. 2017. Functional promoter polymorphisms direct the expression of cystathionine gamma-lyase gene in mouse models of essential hypertension. J Mol Cell Cardiol 102: 61-73. (Cover page article).
46. Kiranmayi M, Chirasani VR, Allu PK, Subramanian L, Martelli EE, Sahu BS, Vishnuprabu D, Kumaragurubaran R, Sharma S, Bodhini D, Dixit M, Munirajan AK, Khullar M, Radha V, Mohan V, Mullasari AS, Naga Prasad SV, Senapati S, Mahapatra NR. 2016. Catestatin Gly364Ser variant alters systemic blood pressure and the risk for hypertension in human populations via endothelial nitric oxide pathway. Hypertension 68:334-347.
45. Kalyani A, Sonawane PJ, Khan AA, Subramanian L, Ehret GB, Mullasari AS, Mahapatra NR. 2015. Post-transcriptional Regulation of Renalase Gene by miR-29 and miR-146 MicroRNAs: Implications for Cardio-metabolic Disorders. J Mol Biol 427: 2629–2646.
44. Gupta V, Khan AA, Sasi BK, Mahapatra NR. 2015. Molecular mechanism of monoamine oxidase A gene regulation under inflammation and ischemia-like conditions: key roles for the transcription factors GATA2, Sp1 and TBP. J Neurochem 134:21-38.
43. Kesh K, Subramanian L, Ghosh N, Gupta V, Gupta A, Bhattacharya S, Mahapatra NR, Swarnakar 2015. Association of MMP7−181A/G promoter polymorphism with gastric cancer risk: Influence of nicotine in differential allele-specific transcription via increased phosphorylation of CREB. J Biol Chem 290:14391-14406.
42. Sonawane PJ, Gupta V, Sasi BK, Kalyani A, Natarajan B, Khan AA, Sahu BS, Mahapatra NR. 2014. Transcriptional Regulation of the Novel Monoamine Oxidase Renalase: Crucial Roles of Transcription Factors Sp1, STAT3 and ZBP89. Biochemistry 53: 6878-6892.
41. Allu PK, Chirasani VR, Ghosh D, Mani A, Bera AK, Maji SK, Senapati S, Mullasari AS, Mahapatra NR. 2014. Naturally occurring variants of the dysglycemic peptide pancreastatin: differential potencies for multiple cellular functions and structure-function correlation. J Biol Chem 289: 4455–4469.
40. Sasi BK, Sonawane PJ, Gupta V, Sahu BS, Mahapatra NR. 2014.Coordinated transcriptional regulation of Hspa1a gene by multiple transcription factors: crucial roles for HSF-1, NF-Y, NF-κB and CREB. J Mol Biol 426:116-35.
39. Friese RS, Altshuler AE, Zhang K, Miramontes-Gonzalez JP, Hightower CM, Jirout ML, Salem RM, Gayen JR, Mahapatra NR, Biswas N, Cale M, Vaingankar SM, Kim HS, Courel M, Taupenot L, Ziegler MG, Schork NJ, Pravenec M, Mahata SK, Schmid-Schönbein GW, O’Connor DT. 2013. MicroRNA-22 and promoter motif polymorphisms at the Chga locus in genetic hypertension: functional and therapeutic implications for gene expression and the pathogenesis of hypertension. Hum Mol Genet 22: 3624-3640.
38. Sahu BS, Mohan J, Sahu G, Allu PKR, Subramanian L, Sonawane PJ, Singh PK, Sasi BK, Senapati S, Maji SK, Bera AK, Gomathi BS, Mullasari AS, Mahapatra NR. 2012. Functional genetic variants of the catecholamine-release-inhibitory peptide catestatin in an Indian population: allele-specific effects on metabolic traits. J Biol Chem 287: 43840-43852 (Featured in Nature India: https://www.natureasia.com/en/nindia/article/10.1038/nindia.2012.177).
37. Sahu BS, Mohan J, Sahu G, Singh PK, Sonawane PJ, Sasi BK, Allu PKR, Maji SK, Bera AK, Senapati S, Mahapatra NR. 2012. Molecular interactions of the physiological anti-hypertensive peptide catestatin with the neuronal nicotinic acetylcholine receptor. J Cell Sci 125: 2323–2337.
36. Friese RS, Ye C, Nievergelt CM, Schork AJ, Mahapatra NR, Rao F, Napolitan PS, Waalen J, Schmid-Schönbein GW, Eskin E, O’Connor DT. 2012. Integrated computational and experimental analysis of the neuroendocrine transcriptome in genetic hypertension identifies novel control points for the cardio-metabolic syndrome. Circ Cardiovasc Genet 5:430-440.
35. Mahata M, Zhang K, Gayen JR, Nandi S, Brar BK, Ghosh S, Mahapatra NR, Taupenot L, O’Connor DT, Mahata SK. 2011. Catecholamine biosynthesis and secretion: physiological and pharmacological effects of secretin. Cell Tissue Res 345:87-102.
34. Sonawane PJ, Sahu BS, Sasi BK, Geedi P, Lenka G, Mahapatra NR. 2011. Functional promoter polymorphisms govern differential expression of HMG-CoA reductase gene in mouse models of essential hypertension. PLoS ONE 6: e16661 (1-16).
33. Abdul Khaliq R, Sonawane PJ, Sasi BK, Sahu BS, Pradeep T, Das SK, Mahapatra NR. 2010. Enhancement in the efficiency of polymerase chain reaction by TiO2 nanoparticles: crucial role of enhanced thermal conductivity. Nanotechnology 21: 255704 (1-11). (Featured in Nature India: https://www.natureasia.com/en/nindia/article/10.1038/nindia.2010.79)
32. Jirout ML, Friese RS, Mahapatra NR, Mahata M, Taupenot L, Mahata SK, Křen V, Zídek V, Fischer J, Maatz H, Ziegler MG, Pravenec M, Hubner N, Aitman TJ, Schork NJ, O’Connor DT. 2010. Genetic regulation of catecholamine synthesis, storage and secretion in the spontaneously hypertensive rat. Hum Mol Genet 19: 2567-2580.
31. Sahu BS, Sonawane PJ, Mahapatra NR. 2010. Chromogranin A: a novel susceptibility gene for essential hypertension. Cell Mol Life Sci 67:861-874.
30. Friese RS, Gayen JR, Mahapatra NR, Schmid-Schonbein G, O’Connor DT, Mahata SK. 2010. Global metabolic consequences of a monogenic model of hypertension: Transcriptomic detection, pathway identification, and experimental verification of dissociated features of the metabolic syndrome. Physiol Genomics 40:195-207.
29. Mahapatra NR. 2008. Catestatin is a novel endogenous peptide that regulates cardiac function and blood pressure. Cardiovasc Res 80:330-338.
28. Vallon V, Eraly SA, Wikoff WR, Rieg T, Kaler G, Truong DM, Ahn SY, Mahapatra NR, Mahata SK, Gangoiti JA, Wu W, Barshop BA, Siuzdak G, Nigam SK. 2008. Organic Anion Transporter 3 Contributes to the Regulation of Blood Pressure. J Am Soc Nephrol 19:1732-1740.
27. Mahapatra NR, Taupenot L, Courel M, Mahata SK, O’Connor DT. 2008. The trans-Golgi proteins SCLIP and SCG10 interact with chromogranin A to regulate neuroendocrine secretion. Biochemistry 47: 7167–7178.
26. Chen Y, Rao F, Rodriguez-Flores JL, Mahapatra NR, Mahata M, Wen G, Salem RM, Shih PA, Das M, Schork NJ, Ziegler MG, Hamilton BA, Mahata SK, O’Connor DT. 2008. Common genetic variants in the chromogranin A promoter alter autonomic activity and blood pressure. Kidney Int 74:115-125.
25. Mahapatra NR, Mahata M, Mahata SK, O’Connor DT. 2006. The chromogranin A fragment catestatin: specificity, potency and mechanism to inhibit exocytotic secretion of multiple catecholamine storage vesicle co-transmitters. J Hypertens 24: 895-904.
24. Greenwood TA, Rao F, Stridsberg M, Mahapatra NR, Mahata M, Lillie EO, Mahata SK, Taupenot L, Schork NJ, O’Connor DT. 2006. Pleiotropic effects of novel trans-acting loci influencing human sympathochromaffin secretion. Physiol Genomics 25: 470-479.
23. Mahapatra NR, Mahata M, Ghosh S, Gayen JR, O’Connor DT, Mahata SK. 2006. Molecular basis of neuroendocrine cell type-specific expression of the chromogranin B gene: crucial role of the transcription factors CREB, AP-2, Egr-1 and Sp1. J Neurochem 99:119-133.
22. Zhang K, Rao F, Wen G, Salem RM, Vaingankar S, Mahata M, Mahapatra NR, Lillie EO, Cadman PE, Friese RS, Hamilton BA, Hook VY, Mahata SK, Taupenot L, O’Connor DT. 2006. Catecholamine storage vesicles and the metabolic syndrome: The role of the chromogranin A fragment pancreastatin. Diabetes Obes Metab 8: 621-633.
21. Mahapatra NR, O’Connor DT, Vaingankar SM, Sinha Hikim AP, Mahata M, Ray S, Staite E, Wu H, Gu Y, Dalton N, Kennedy BP, Ziegler MG, Ross J, Mahata SK. 2005. Targeted ablation of the chromogranin A gene: Elevated blood pressure rescued by the human ortholog. J Clin Invest 115: 1942-1952. (With editorial commentary).
20. Friese RS, Mahboubi P, Mahapatra NR, Mahata SK, Schork NJ, Schmid-Schoenbein GW, O’Connor DT. 2005. Common genetic mechanisms of blood pressure elevation in two independent rodent models of human essential hypertension. Am J Hypertens 18: 633-652.
19. Ghosh S, Mahapatra NR, Nandi S, Banerjee PC. 2005. Integration of metal-resistant determinants from the plasmid of an Acidocella strain into the chromosome of Escherichia coli DH5α. Curr Microbiol 50: 28-32.
18. Mahata SK, Mahata M, Wen G, Wong WB, Mahapatra NR, Hamilton BA, O’Connor DT. 2004. The catecholamine release-inhibitory “catestatin” fragment of chromogranin A: naturally occurring human variants with different potencies for multiple chromaffin cell nicotinic cholinergic responses. Mol Pharmacol 66: 1180-1191.
17. Mahapatra NR, Mahata M, Hazra PP, McDonough PM, O’Connor DT, Mahata SK. 2004. A dynamic pool of calcium in catecholamine storage vesicles: Exploration in living cells by a novel vesicle-targeted chromogranin A/aequorin chimeric photoprotein. J Biol Chem 279: 51107-51121.
16. Fries RS, Mahboubi P, Mahapatra NR, Mahata SK, Schork NJ, Schmid-Schoenbein GW, O’Connor DT. 2004. Neuroendocrine transcriptome in genetic hypertension: multiple changes in diverse adrenal physiological systems. Hypertension 43: 1301-1311.
15. Wen G, Mahata SK, Cadman P, Mahata M, Ghosh S, Mahapatra NR, Rao F, Stridsberg M, Smith DW, Mahboubi P, O’Connor DT, Hamilton BA. 2004. Both rare and common polymorphisms contribute functional variation at CHGA, a regulator of catecholamine physiology. Am J Hum Genet 74: 197-207. (Lead article).
14. Preece NE, Nguyen M, Mahata M, Mahata SK, Mahapatra NR, Tsigelny I, O’Connor DT. 2004. Conformational preferences and activities of peptides from the catecholamine release-inhibitory (catestatin) region of chromogranin A. Regul Pept 118: 75-87.
13. Mahapatra NR, Ghosh S, Sarkar PK, Benerjee PC. 2003. Generation of novel plasmids in Escherichia coli S17-1(pSUP106). Curr Microbiol 46: 318-323.
12. Mahata SK, Mahapatra NR, Mahata M, Wang TC, Kennedy BP, Ziegler MG, O’Connor DT. 2003. Catecholamine secretory vesicle stimulus-transcription coupling in vivo: demonstration by a novel transgenic promoter/photoprotein reporter, and inhibition of secretion and transcription by the chromogranin A fragment catestatin. J Biol Chem 278: 32058-32067.
11. Wong C*, Mahapatra NR*, Chitbangonsyn S, Mahboubi P, Mahata M, Mahata SK, O’Connor DT.2003. The angiotensin II receptor (Agtr1a): Functional regulatory polymorphisms in a locus genetically linked to blood pressure variation in the mouse. Physiol Genomics 14: 83-93.[*equal contribution].
10. Mahapatra NR, Mahata M, O’Connor DT, Mahata SK. 2003. Secretin activation of chromogranin A gene transcription: identification of the signaling pathways in cis and in trans. J Biol Chem 278: 19986-19994.
9. Taupenot L, Harper KL, Mahapatra NR, Parmer RJ, Mahata SK, O’Connor DT. 2002. Identification of a novel sorting determinant for the regulated pathway in the secretory protein chromogranin A. J Cell Sci 115: 4827-4841.
8. Mahata M, Mahapatra NR, O’Connor DT, Mahata SK. 2002. Chromaffin cell catecholamine secretion: bisindolylmaleimide compounds exhibit novel and potent antagonist effects at the nicotinic cholinergic receptor in pheochromocytoma cells. Mol Pharmacol 61: 1340-1347.
7. Taupenot L, Harper KL, Mahapatra NR, Parmer RJ, O’Connor DT. 2002. Intracellular protein trafficking into catecholamine storage vesicles: novel chimeric photoproteins visualized by deconvolution fluorescence microscopy. Ann N Y Acad Sci 971: 262-265.
6. Mahapatra NR, Ghosh S, Deb C, Banerjee PC. 2002. Resistance to cadmium and zinc in Acidiphilium symbioticum KM2 is plasmid mediated. Curr Microbiol 45:180-186.
5. Mahata SK, Mahapatra NR, Mahata M, O’Connor DT. 2002. Neuroendocrine cell type-specific and inducible expression of chromogranin/secretogranin genes: crucial promoter motifs. Ann N Y Acad Sci 971: 27-39.
4. Ghosh S, Mahapatra NR, Banerjee PC. 2000. Plasmid curing from an acidophilic bacterium of the genus Acidocella. FEMS Microbiol Lett 183: 271-274.
3. Mahapatra NR, Mahata M, Datta A, Gerdes H -H, Huttner WB, O’Connor DT, Mahata SK. 2000. Neuroendocrine cell type-specific and inducible expression of the chromogranin B gene: crucial role of the proximal promoter. Endocrinology 141: 3668-3678.
2. Ghosh S, Mahapatra NR, Banerjee PC. 1997. Metal resistance in Acidocella strains and plasmid mediated transfer of this characteristic to Acidiphilium multivorum and Escherichia coli. Appl Environ Microbiol 63: 4523-4527.
1. Mahapatra NR, Banerjee PC. 1996. Extreme tolerance to cadmium and high resistance to copper, nickel and zinc in different Acidiphilium strains. Lett Appl Microbiol 23: 393-397.
II. Book Chapters.
3. Sonawane PJ, Sahu BS, Mahapatra NR. 2011. Pharmacogenomics of cardiovascular drugs. In: Drug Design-Basics and Applications (Doble M, Ed.). pp. 280-310. Tata-McGraw-Hill Publishers, New Delhi, India.
2. Ghosh S, Mahapatra NR, Saha A, Banerjee PC. 2002. Transformation of Escherichia coli XLI-Blue with plasmids of the acidophilic heterotrophic strain Acidocella sp. GS19h: Novel plasmid generation and identification of insertion elements. In: Mineral Biotechnology (Sukla LB & Misra VN, Eds) pp. 67-73. Allied Publishers Pvt. Ltd., New Delhi, India.
1. Ghosh S, Mahapatra NR, Banerjee PC. 1999. Cloning of metal-resistance conferring genes from an Acidocella strain. In: Biohydrometallurgy and the Environment toward the Mining of 21th century (Amils R & Ballester A, Eds), Process Metallurgy Series (no.9, part B), pp.21-28. Elsevier, Amsterdam, The Netherlands.