Syamal K. Bhattacharya, Ph.D.
Department of Medicine, Surgery, Neurology, and Pharmaceutical Sciences
NIH-Sponsored Medical Students Research Program
The University of Tennessee
Health Science Center
Department of Medicine, Division of Cardiovascular Diseases
956 Court Avenue, Suite B318
Memphis, TN 38163
Phone: (901) 448-5676
Fax: (901) 448-8077
Lab: B315 Coleman Bldg.
Email: Syamal K. Bhattacharya
- Ph.D. Institution: University of Memphis, Department of Chemistry
My work over three decades remained focused on the study of membrane-mediated Ca2+-induced cellular degeneration in cardiovascular and neuromuscular diseases, both in humans and animals, with a special emphasis on the mechanisms and regulation of excessive intracellular Ca2+ accumulation (EICA), cellular energetics and cell death. Aspects of other intracellular events that transpire in the degenerating dystrophic myofibers, such as elevation in myoplasmic free [Ca2+] and mitochondrial (MIT) Ca2+-overloading; loss of sarcolemmal dystrophin, dystrophin-associated glycolproteins and sarcoglycans; dysregulation of slow Ca2+-channels with reduced Ca2+-pumping out of the cells and its sarcoplasmic reticulum (SR) and their gene expressions; structural and functional impairments of MIT&SR, and their Na+/Ca2+ exchangers; as well as light microscopic & ultrastructural aberrations in MIT/SR, are also of considerable interest.
Other ongoing studies include: 1) Cellular-molecular mechanisms of intracellular translocations of Ca2+, Mg2+ and Zn2+ to injured soft tissues in chronic aldosteronism that eventuate in an immunostimulatory state and a vascular phenotype involving the coronary and systemic vasculatures; 2) Role of PTH in the genesis of aldosterone-mediated low-renin hypertension and congestive heart failure (CHF) with EICA in the cardiac/skeletal muscles, myocardial remodeling with fibrosis, and severe bone loss; 3) Pharmacologic regulation of cardiac lesions with EICA, oxidative stress, associated pathobiology and cellular morphology in CHF by aldosterone receptor blockers, Ca2+-channel blockers, antioxidants and diuretics; 4) Intrinsically coupled Ca2+ and Zn2+ dyshomeostasis linked to secondary hyperparathyroidism, EICA, oxidative stress, and hypovitaminosis-D in patients with CHF, dilated and hypertrophic cardiomyopathy; and 5) Mitochondria-targeted cardioprotective strategies using carvedilol (inhibitor of mitochondrial Ca2+ uniporter), cyclosporine-A (potent mPTP inhibitor) and quercetin (MIT-specific antioxidant) in acute and chronic stressor states such as MI and CHF.
Using molecular biological approaches and in vivo and in vitro myogenic cell culture systems of dystrophic origin, the roles of genetic perturbations in subsarcolemmal structural proteins (dystrophin, α-, β-, γ-, δ-sarcoglycans, utrophin) and the consequent membrane-mediated EICA have been explored thoroughly to unravel the pathogenic mechanisms involved in hereditary muscular dystrophy (HMD). Mitigation of EICA in HMD with cardiomyopathy is being optimized in dystrophic myoblasts and myotubes by regulating transmembrane L-type Ca2+-channels and intracellular Ca2+-pumping using slow Ca2+-channel blockers, antioxidants and membrane stabilizers. Similar studies in myogenic cells of Duchenne muscular dystrophic (DMD) origin, or those from analogous animal models, are being proposed to enhance our understanding of the underlying cellular and molecular cascades responsible for progressive cardiac and skeletal muscle degeneration in DMD and other forms of HMD.
Therapeutic trials in HMD with a variety of pharmacologic agents were carried out in our laboratories during 1979-2003, with an aim to slow the dystrophic pathobiology and lengthen the shorter life span. On the premise of our provocative findings of multiple salutary effects of diltiazem, a slow Ca2+-channel blocker, in hamsters with HMD and cardiomyopathy (Muscle & Nerve, 5:73-78, 1982; ibid., 10:168-176, 1987; J Neurol Sci., 115:76-90, 1993; ibid., 120:180-6, 1993; Mol Chem Neuropathol, 31:187-206, 1997; ibid., 34:53-77, 1998; Mol Cell Biochem, 238:119-127, 2002), we are aspiring to launch a long-term, double-blind, placebo-controlled clinical trial in very young boys with DMD.
- Weber KT, Sun Y, Bhattacharya SK, Ahokas RA, Gerling IC. Myofibroblast-mediated mechanisms of pathological remodelling of the heart. Nat Rev Cardiol. 2013 Jan;10(1):15-26. doi: 10.1038/nrcardio.2012.158. Epub 2012 Dec 4. PubMed PMID: 23207731.
- Seawell MR, Al Darazi F, Farah V, Ramanathan KB, Newman KP, Bhattacharya SK, Weber KT. Mineralocorticoid receptor antagonism confers cardioprotection in heart failure. Curr Heart Fail Rep. 2013 Mar;10(1):36-45. doi: 10.1007/s11897-012-0120-x. PubMed PMID: 23114591; PubMed Central PMCID: PMC3568253.
- Yusuf J, Khan MU, Cheema Y, Bhattacharya SK, Weber KT. Disturbances in calcium metabolism and cardiomyocyte necrosis: the role of calcitropic hormones. Prog Cardiovasc Dis. 2012 Jul-Aug;55(1):77-86. doi: 10.1016/j.pcad.2012.02.004. Review. PubMed PMID: 22824113; PubMed Central PMCID: PMC3404408.
- Cheema Y, Zhao W, Zhao T, Khan MU, Green KD, Ahokas RA, Gerling IC, Bhattacharya SK, Weber KT. Reverse remodeling and recovery from cachexia in rats with aldosteronism. Am J Physiol Heart Circ Physiol. 2012 Aug 15;303(4):H486-95. doi: 10.1152/ajpheart.00192.2012. Epub 2012 Jun 22. PubMed PMID: 22730385; PubMed Central PMCID: PMC3423147.
- Rutledge MR, Farah V, Adeboye AA, Seawell MR, Bhattacharya SK, Weber KT. Parathyroid hormone, a crucial mediator of pathologic cardiac remodeling in aldosteronism. Cardiovasc Drugs Ther. 2013 Apr;27(2):161-70. doi: 10.1007/s10557-012-6378-0. PubMed PMID: 22373564.
- Khan MU, Cheema Y, Shahbaz AU, Ahokas RA, Sun Y, Gerling IC, Bhattacharya SK, Weber KT. Mitochondria play a central role in nonischemic cardiomyocyte necrosis: common to acute and chronic stressor states. Pflugers Arch. 2012 Jul;464(1):123-31. doi: 10.1007/s00424-012-1079-x. Epub 2012 Feb 11. Review. PubMed PMID: 22328074; PubMed Central PMCID: PMC3386379.