Sudhiranjan Gupta, PhD
Education and Post-Graduate Training
BSc, University of Burdwan, West Bengal, India, 1987
MS, Visva Bharati University, Santiniketan, India, 1990
PhD, Molecular Biology, Bose Institute, Calcutta, India, 1991-1997
Our current research interests include transcription factor mediated microRNA (miRNA) modulation in cardiovascular diseases. Using miRNA array and miRNA next generation sequencing analysis, we have identified a panel of novel miRNAs in transthoracic aortic constriction (TAC), Ang II-induced cardiac remodeling and monocrotaline-induced pulmonary hypertension in mice. Our long-term goal is to establish a comprehensive model of NF-kB regulated miRNA gene-networks in the heart and lungs for better therapeutic use.
Molecular analysis of NF-kB-mediated miRNA modulation in cardiac remodeling
Cardiac remodeling is a process that alters structural and functional determinants of myocardium in response to hemodynamic stress or pressure overload. The resulted phenomena exhibit as left ventricular hypertrophy, fibrosis and contractile dysfunction leading to heart failure. Nuclear factor-kB (NF-kB) is a pleiotropic transcription factor plays a fundamental role in immunity, but also regulates varieties of genes expression in cardiac diseases like myocardial infarction, ischemia-reperfusion injury or left ventricular hypertrophy. Therefore, targeting NF-kB as well as its related signaling pathways has been considered as a potential therapeutic target for the treatment of cardiac diseases. Recent studies including ours provide clear evidence that a small non-coding RNA molecule designated as micro RNAs (miRNAs) play important roles by fine-tuning gene expression in response to physiological or pathological stress. We have identified a panel of novel dysregulated miRNAs in the left ventricle of wild-type mice subjected to thoracic aortic constriction (TAC) and Angiotensin II infusion. The dysregulated miRNAs were restored in cardiac-specific IkBa triple-mutant transgenic mice subjected to TAC, indicated NF-kB-dependent regulation. As both NF-kB and miRNA are important regulators in cardiac diseases, we envision that NF-kB-targeting miRNAs would serve as potential therapeutics module for the treatment of cardiac hypertrophy and fibrosis. Our laboratory uses a myriad of tools and techniques including stem cells, in vivo mouse models and cutting edge molecular biology techniques. Using next generation sequencing analysis, we further discovered a set of novel dysregulated miRNAs in Angiotensin II induced cardiac remodeling.
Molecular basis of NF-kB-mediated miRNA modulation in Pulmonary Arterial Hypertension and right ventricular hypertrophy
Pulmonary arterial hypertension (PAH) is characterized by multicellular vascular lesions which obstruct and obliterate pulmonary arteries. The occluded vessels impede blood flow and increase right ventricular afterload leading to right ventricular hypertrophy (RVH), fibrosis and RV failure. We demonstrated that monocrotaline (MCT) treated PAH-induced RVH was attenuated in a cardiac specific IkBa triple mutant transgenic mice (3M), compared to wild type mice, suggesting a protective role of NF-kB in RVH. We identified a panel of novel dysregulated miRNAs in the RV and lungs of the MCT treated WT mice, all targets of the BMP-SMAD-Id-Notch signaling axis. Alterations of the above miRNAs were restored in the RV of MCT treated 3M mice, indicating NF-kB-mediated regulation in PAH-induced RVH. We identified BMPRII-SMAD-Id-Notch signaling axis, a critical contributor in the development of PAH and RVH. We further demonstrated for the first time that lung specific inhibition of NF-kB prevented MCT induced PAH and RVH. Using miRNA array analysis, we identified novel miRNAs in the lungs and RV of MCT-induced PAH. We are currently investigating how miRNAs can protect the vascular bed and understanding the mechanism of miRNA action points to therapeutic targets for development of new intervention in PAH and RVH.
- Li L, Bound K, Chatterjee, K, Gupta S. MicroRNA-130a, a potential for antifibrotic target in cardiac fibrosis. J Am Heart Assoc 2017 (in press).
- Li L, Kim IK, Chiasson V, Chatterjee P, Gupta S. NF-kB mediated miR-130a modulation in lung microvascular cell: implication in pulmonary hypertension. Exp Cell Res. 2017;359(1):235-242. doi: 10.1016/j.yexcr.2017.07.024. PMID: 28755990
- Li L, Wei C, Kim IK, Janssen-Heininger Y, Gupta S. Inhibition of nuclear factor-kB in the lungs prevents monocrotaline-induced pulmonary hypertension in mice. Hypertension. 2014 Jun;63(6):1260-9. doi: 10.1161/HYPERTENSIONAHA.114.03220. PMID: 24614212
- Wei C, Kim IK, Kumar S, Jayasinghe S, Hong N, Castoldi G, Catalucci D, Jones WK, Gupta S. NF-kB mediated miR-26a regulation in cardiac fibrosis. J Cell Physiol. 2013 Jul;228(7):1433- 42. doi: 10.1002/jcp.24296. PMID: 23254997
- Wei C, Henderson H, Spradley C, Li L, Kim IK, Kumar S, Hong N, Arroliga AC, Gupta S. Circulating miRNAs as potential marker for pulmonary hypertension. PLoS One. 2013 May;8(5):e64396. doi: 10.1371/journal.pone.0064396. PMID: 23717609; PMCID: PMC3662705
- Kumar S, Wei C, Thomas CM, Kim IK, Seqqat R, Kumar R, Baker KM, Jones WK, Gupta S. Cardiac-specific genetic inhibition of nuclear factor-kB prevents right ventricular hypertrophy induced by monocrotaline. Am J Physiol Heart Circ Physiol. 2012 Apr 15;302(8):H1655–66. doi: 10.1152/ajpheart.00756.2011. PMID: 22245771
- Kumar S, Seqqat R, Chigurupati S, Kumar R, Baker KM, Young D, Sen S, Gupta S. Inhibition of nuclear factor kB regresses cardiac hypertrophy by modulating the expression of extracellular matrix and adhesion molecules. Free Radic Biol Med. 2011 Jan 1;50(1):206-15. doi: 10.1016/j.freeradbiomed.2010.10.711. PMID 21047552
- Fukuda K, Gupta S, Chen K, Wu C, Qin J. The pseudoactive site of ILK is essential for its binding to alpha-Parvin and localization to focal adhesions. Mol Cell. 2009 Dec 11;36(5):819-30. doi: 10.1016/j.molcel.2009.11.028. PMID: 20005845; PMCID: PMC2796127
- Gupta S, Young D, Maitra RK, Gupta A, Popovic ZB, Yong SL, Mahajan A, Wang Q, Sen S. Prevention of cardiac hypertrophy and heart failure by silencing of NF-kappaB. J Mol Biol. 2008 Jan 18;375(3):637-49. doi: 10.1016/j.jmb.2007.10.006. PMID: 18037434; PMCID: PMC2277468
- Gupta S, Purcell NH, Lin A, Sen S. Activation of nuclear factor-kappaB is necessary for myotrophin-induced cardiac hypertrophy. J Cell Biol. 2002 Dec 23;159(6):1019-28. doi: 10.1083/jcb.200207149. PMID: 12486112; PMCID: PMC2173971