In the lab, we study thrombosis and fibrosis, two leading causes of death worldwide in patients with cardiovascular disease and cancer. Thrombosis, which occurs when blood clots inside blood vessels, can lead to heart attack or stroke. Fibrosis, or the formation of scar tissue, can damage the heart muscle and other tissues.
Blood clotting is a natural mechanism in the body that prevents blood loss when there is a wound, cut or trauma, but when it occurs inside the blood vessels, it can block blood supply to major organs. This can cause heart attacks, stroke and many thrombotic complications associated with cancer.
We also study TGF Beta, a multifunctional protein generated by blood platelets that contributes to many different disease conditions, including cancer, autoimmune diseases and fibrosis. However, the role of platelet-derived TGF Beta has not been clearly defined in the progression of these disease conditions.
Our lab also studies HIV and antiretroviral (ART) drug-induced organ fibrosis. Everyone with HIV has elevated levels of fibrosis, but those who are undergoing treatment have even more. The factors involved in causing HIV-related fibrosis are not yet clear. Because TGF Beta is a major inducer of cardiac fibrosis, our lab will focus on identifying whether platelet TGF Beta contributes to elevated fibrosis observed in HIV and HIV ART-treated patients.
Transforming growth factor-β1 (TGF-β1) is a multifunctional cytokine with important roles in cellular proliferation, differentiation, the immune response, and many other biological functions, including synthesis of the matrix protein collagen in wound repair as well as pathological fibrosis in cancer and cardiovascular diseases. In addition to its generation in the tissues, TGF-β1 circulates in the bloodstream where it has the potential to produce systemic effects, but the sources of circulating TGF-β1 remain to be defined. TGF-β1 is produced by almost all cell types, but platelets contain ~100 times more than any other cells. TGF-β1 is secreted as an inactive, latent complex, and defining its activation mechanism in vivo is one of the subjects of our research. We recently demonstrated that shear force activates TGF-β1 release from platelets in vitro and during thrombus formation in mouse carotid artery in vivo. These data indicate that shear force is a potential mechanism for systemic activation of TGF-β1 in disease states associated with high circulatory shear force.
Our hypothesis is that release and activation of TGF-β1 occurs in vivo in clinical disorders involving organ fibrosis and high circulatory shear stress. These include severe aortic stenosis (AS), in which high shear is generated across the stenotic valve, and end-stage heart failure patients implanted with left ventricular assist devices (LVAD), which generate high shear through the device’s spinning rotor.
AS is a major cause of morbidity and mortality in the elderly, as the shear stress across the stenotic valve is very high and the only available treatment is aortic valve replacement surgery. Circulating TGF-β1 levels are elevated in individuals with AS, but the source of TGF-β1 and its activation mechanism are not clear. Our hypothesis is that TGF-β1 released from platelets and activated by shear across the narrowed aortic valve contributes to AS progression by initiating fibrosis and calcification in the aortic valve.
Heart failure is also a serious problem among the aging US population. While heart transplant is an option for some, the donor supply is limited and many patients die before transplant. LVADs have tremendously improved survival, but LVAD recipients are at high risk for thrombohemorrhagic events and aortic valve fusion and there are, as yet, no validated biomarkers predictive of these complications.We hypothesize that high shear generated by the LVAD activates platelets that then release TGFβ1 in the circulation, suggesting that plasma TGF-β1 levels may be a valuable biomarker of thrombotic risk.
B.Sc., Human Physiology, University of Calcutta, India, 1991
M.Sc., Human Physiology, University of Calcutta, India, 1993
Ph.D., Biochemistry and Physiology, Bose Institute/University of Calcutta, Kolkata, India, 2000
Honors and Awards
1993 Gold Medal Award in Biophysics and Physiology, Physiological Society of India
2004 Post-Doctoral Fellowship Award, The American Heart Association
2008 New York City Community Trust Grant Award, NY
2009 Irma T. Hirschl and Monique Weill-Caulier Trust Grant Award, NY
2010 Associate Faculty Member of the Faculty of 1000 in Biology, London, U.K.
2011 Invited Speaker at the Scientific Committee on Platelets, American Society of Hematology
Joined OMRF Scientific Staff 2015
Elhadad S, Chapin J, Copertino D, Van Besien K, Ahamed J, Laurence J. MASP2 levels are elevated in thrombotic microangiopathies: Association with microvascular endothelial cell injury and suppression by anti-MASP2 antibody narsoplimab. Clin Exp Immunol, 2020 July, PMID: 32681658, PMCID: PMC7405159
Laurence J, Elhadad S, Gostynska S, Yu Z, Terry H, Varshney R, Fung KM, Choi ME, Ahamed J. HIV protease inhibitor ritonavir induces renal fibrosis and dysfunction: role of platelet-derived TGF-β1 and intervention via anti-oxidant pathways. AIDS, 2020 March, PMID: 32167970, PMCID: PMC7210074
Kouzbari K, Hossan MR, Arrizabalaga JH, Varshney R, Simmons AD, Gostynska S, Nollert MU, Ahamed J. Oscillatory shear potentiates latent TGF-β1 activation more than steady shear as demonstrated by a novel force generator. Sci Rep 9:6065, 2019 April, PMID: 30988341, PMCID: PMC6465594
Ahamed J, Terry H, Choi ME, Laurence J. Transforming growth factor-β1-mediated cardiac fibrosis: potential role in HIV and HIV/antiretroviral therapy-linked cardiovascular disease. AIDS. 2016 Feb 20;30(4):535-42. PMID: 26605511 PMCID: PMC4738098
Zhao M, Perry JM, Marshall H, Venkatraman A, Qian P, He XC, Ahamed J, Li L. Megakaryocytes maintain homeostatic quiescence and promote post-injury regeneration of hematopoietic stem cells. Nat Med. 2014 Nov;20(11):1321-6. PMID: 25326798
Wang W, Vootukuri S, Meyer A, Ahamed J, Coller BS. Association between shear stress and platelet-derived transforming growth factor-β1 release and activation in animal models of aortic valve stenosis. Arterioscler Thromb Vasc Biol. 2014 Sep;34(9):1924-32. PMID: 24903096 PMCID: PMC4141006
Brophy TM, Coller BS, Ahamed J. Identification of the thiol isomerase-binding peptide, mastoparan, as a novel inhibitor of shear-induced transforming growth factor beta1 (TGF-beta1) activation. J Biol Chem 288: 10628-10639, 2013. PMID: 23463512 PMCID: PMC3624443
Meyer A, Wang W, Qu J, Croft L, Degen JL, Coller BS, Ahamed J. Platelet TGF-beta1 contributions to plasma TGF-beta1, cardiac fibrosis, and systolic dysfunction in a mouse model of pressure overload. Blood 119: 1064-1074, 2012. PMID: 22134166 PMCID: PMC3271718
Cardiovascular Biology Research Program, Mail Stop 45
825 NE 13th Street
Oklahoma City, Oklahoma 73104
Phone: (405) 271-2560
Lab Phone: (405) 271-2564
Fax: (405) 271-3137