Shanmugam Nagarajan, PhD
Shan Nagarajan, PhD
S-408 BST South
Dr. Nagarajan is a member of the Department of Pathology, Division of Experimental Pathology, a Principal Investigator in the Vascular Medicine Institute, and a member of the Cellular and Molecular Pathology Graduate Training Program.
|MSc||1982||Christian Medical College, Vellore, and University of Madras, India|
|PhD||1988||Christian Medical College, Vellore, and University of Madras, India|
There are three major areas of research in Dr. Nagarajan's laboratory. In the first project my laboratory is investigating the role of auto-antibodies, specifically antibody against oxLDL in the initiation and progression of atherosclerosis. Moreover because of the central role of modulation of immune system in chronic diseases, his laboratory is interested in understanding the role of immune system in pathophysiology of atherosclerosis. Recent studies have suggested that generation of oxidative products of LDL (oxLDL) is one of the risk factors implicated in the pathogenesis of atherosclerosis. OxLDL induces an autoimmune response as evidenced by the presence of anti-oxLDL IgG in atherosclerotic lesions in patients and animal models. Moreover the titer of autoantibodies against oxLDL correlates with the progression of atherosclerosis in humans and in the hyperlipidemic mouse model. This raises a possibility that in oxLDL-immune complexes binding to Fcγ receptors (FcγR) may contribute to the progression of atherosclerosis. These receptors also play a major role in IC-mediated tissue injury in autoimmune inflammatory disease. FcγRs are classified into activating and inhibitory receptors. Activating FcγRs are involved in cellular functions such as phagocytosis of antibody-opsonized particles, and inflammatory responses. The inhibitory FcγR (CD32B) regulates the inflammatory response initiated by the activating FcγRs and control antibody production by regulating B lymphocyte activation. OxLDL-IC generated during hyperlipidemia could bind to the activating and/or inhibitory FcγRs present in human atherosclerotic lesions and contribute to the inflammatory processes. The central hypothesis of our research focus is that FcγRs play an important role in the progression of atherosclerosis.
In the second project Dr. Nagarajan’s research centers on the global issue of how dietary factors modulate the immune system to prevent chronic inflammatory diseases including atherosclerosis. Epidemiological reports suggest that cardiovascular incidence is lower in Asian population. It is plausible that the diets such as soy and rice may modulate the immune system, thus preventing atherosclerotic lesions. In recent studies we have determined that the progression of atherosclerotic lesions were strikingly reduced in soy protein fed hyperlipidemic animal models. There are two major components with potential bioactivity in soy diet or soy protein isolates: phytochemicals such as isoflavones associated with soy protein, and peptides generated from two of the major soy proteins such as β-conglycinin (or 7S globulins) and glycinin (or 11S globulins). We have recently identified isoflavone-free soy protein inhibits the progression of atherosclerosis by blocking inflammatory cytokine/chemokine responses and inflammation induced VCAM-1 expression. Interestingly, maternal hypercholesterolemia has been implicated with a higher incidence and earlier onset of atherosclerotic lesions in neonatal offspring. Currently, we are investigating whether in utero exposure to isoflavone-free soy protein isolate (SPI—) diet primes the vessel wall to attenuate development of atherosclerosis in adult life of F1 offspring. Specifically we are studying the effect of in utero dietary exposure of soy or soy derived compounds in preventing chronic inflammatory diseases such as atherosclerosis.
Recent studies have suggested that pathogen-induced inflammation at sites distant from the infection site contributes to the initiation and progression of atherosclerosis. The contribution of urogenital infection with C. muridarum has never been studied in cardiovascular pathogenesis. Recently we have undertaken studies to determine the causal link between genital Chlamydia induced inflammatory responses promoting atherosclerosis. Preliminary studies have established Chlamydia genital infection results in enhanced atherosclerosis in hyperlipidemic mouse models. Currently we are pursuing studies to understand molecular mechanism(s) contributing to the enhanced atherosclerosis during genital Chlamydia infection.
Selvaraj P, Fifadara N, Nagarajan S, Cimino A, Wang G. Functional regulation of human neutrophil Fcγ receptors. Immunologic research. 2004; 29 (1):219-30.
Nagarajan S, Stewart BW, Badger TM. Soy isoflavones attenuate human monocyte adhesion to endothelial cell-specific CD54 by inhibiting monocyte CD11a. Journal of Nutrition. 2006 Sep; 136 (9):2384-90.
Li P, Jiang N, Nagarajan S, Wohlhueter R, Selvaraj P, Zhu C. Affinity and kinetic analysis of Fcgamma receptor IIIa (CD16a) binding to IgG ligands. Journal of Biological Chemistry. 2007 Mar 2; 282 (9):6210-21.
Nagarajan S, Burris RL, Stewart BW, Wilkerson JE, Badger TM. Dietary soy protein isolate ameliorates atherosclerotic lesions in apolipoprotein E-deficient mice potentially by inhibiting monocyte chemoattractant protein-1 expression. Journal of Nutrition. 2008 Feb; 138 (2):332-7.
Thampi P, Stewart BW, Joseph L, Melnyk SB, Hennings LJ, Nagarajan S. Dietary homocysteine promotes atherosclerosis in apoE-deficient mice by inducing scavenger receptors expression. Atherosclerosis. 2008 Apr; 197 (2):620-9.
Nagarajan UM, Prantner D, Sikes JD, Andrews CW Jr, Goodwin AM, Nagarajan S, Darville T. Type I interferon signaling exacerbates Chlamydia muridarum genital infection in a murine model. Infection and immunity. 2008 Oct; 76 (10):4642-8.
Nagarajan S. Mechanisms of anti-atherosclerotic functions of soy-based diets. The Journal of Nutritional Biochemistry. 2010 Apr; 21 (4):255-60. (INVITED)
Burris RL, Xie CH, Thampi P, Wu X, Melnyk SB, Nagarajan S. Dietary rice protein isolate attenuates atherosclerosis in apoE-deficient mice by upregulating antioxidant enzymes. Atherosclerosis. 2010 Sep; 212 (1):107-15.
Wu X, Kang J, Xie C, Burris R, Ferguson ME, Badger TM, Nagarajan S. Dietary blueberries attenuate atherosclerosis in apolipoprotein E-deficient mice by upregulating antioxidant enzyme expression. Journal of Nutrition. 2010 Sep; 140 (9):1628-32.
Xie C, Kang J, Burris R, Ferguson ME, Schauss AG, Nagarajan S, Wu X. Açaí juice attenuates atherosclerosis in ApoE deficient mice through antioxidant and anti-inflammatory activities. Atherosclerosis. 2011 Jun; 216 (2):327-33.
Xie C, Ng H, Nagarajan S. OxLDL or TLR2-induced cytokine response is enhanced by oxLDL-independent novel domain on mouse CD36. Immunology Letters. 2011 Jun 30; 137 (1):15-27. PMCID: PMC3078215.
Xie C, Kang J, Ferguson ME, Nagarajan S, Badger TM, Wu X. Blueberries reduce pro-inflammatory cytokine TNF-a and IL-6 production in mouse macrophages by inhibiting NF-kB and the MAPK pathway. Molecular Nutrition & Food Research. 2011 Sep 2.
Xie C, Kang J, Chen JR, Lazarenko OP, Ferguson ME, Badger TM, Nagarajan S, Wu X. Lowbush blueberries inhibit scavenger receptors CD36 and SR-A expression and attenuate foam cell formation in ApoE-deficient mice. Food & function. 2011 Sep 28.
Xie C, Kang J, Chen JR, Nagarajan S, Badger TM, Wu X. Phenolic acids are in vivo atheroprotective compounds appearing in the serum of rats after blueberry consumption. Journal of agricultural and food chemistry. 2011 Sep 28; 59 (18):10381-7.
Xie C, Kang J, Li Z, Schauss AG, Badger TM, Nagarajan S, Wu T, Wu X. The açaí flavonoid velutin is a potent anti-inflammatory agent: blockade of LPS-mediated TNF-a and IL-6 production through inhibiting NF-κB activation and MAPK pathway. Journal of Nutritional Biochemistry. 2011
Ng HP, Burris RL, Nagarajan S. Attenuated atherosclerotic lesions in apoE-Fcγ-chain-deficient hyperlipidemic mouse model is associated with inhibition of Th17 cells and promotion of regulatory T cells. Journal of immunology . 2011 Dec 1; 187 (11):6082-93.
Owens AP 3rd, Passam FH, Antoniak S, Marshall SM, McDaniel AL, Rudel L, Williams JC, Hubbard BK, Dutton JA, Wang J, Tobias PS, Curtiss LK, Daugherty A, Kirchhofer D, Luyendyk JP, Moriarty PM, Nagarajan S, Furie BC, Furie B, Johns DG, Temel RE, Mackman N. Monocyte tissue factor-dependent activation of coagulation in hypercholesterolemic mice and monkeys is inhibited by simvastatin. Journal of Clinical Investigation. 2012 Feb 1; 122 (2):558-68.