Ahamed Lab

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.

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