Heart failure (HF) is a progressive syndrome affecting nearly 20 million people worldwide and is generally caused by remodeling of the heart in response to pathological stress. Emerging evidence associates systemic inflammation with left ventricular (LV) dysfunction and HF, but the mechanisms for the observed systemic inflammation are largely unexplored. Our preliminary data using Thoracic aortic constriction (TAC), a well-defined model of HF, indicates that T cells are recruited to the heart and the heart vascular endothelium is activated locally as LV function worsens. Interestingly, we found that T cells from mice undergoing HF interact with activated mouse heart endothelial cells in significant higher numbers than T cells from control mice under physiological flow conditions in vitro. Remarkably, T cell deficient mice (TCR?-) showed increased survival, preserved LV function, and decreased fibrosis in our pilot studies. Based on these data, in this proposal we will test the central hypothesis that T cell mediated immune responses influence cardiac remodeling in pressure overload induced HF. We propose 3 specific aims to test this hypothesis, in which we will obtain novel information about the mechanisms regulating mouse and human T cell recruitment in the heart during the course of HF, the T cell subsets involved, and their influence in the mechanisms regulating cardiac remodeling in HF.
In Aim 1 we will use videomicroscopy to study the adhesion mechanisms regulating interactions between mouse T cells and heart endothelial cells during the progression of HF induced by TAC, determining if T cells from mice with HF utilize selectin and/or integrin/Ig superfamily pathways, to mediate rolling, arrest and transendothelial migration under physiological flow conditions in vitro. The expression and functionality of adhesion molecules and chemokine receptors in T cells from mice with HF will also be characterized by flow cytometry.
Aim 2 will characterize the T cell mediated immune response induced by TAC, define the role of T cell subsets during the progression of HF, and their role in cardiomyocyte and cardiac fibroblast function in vitro. TAC studies will be performed in WT and TCR?- mice and different T cell subsets will be adoptively transferred into TCR?- recipient mice undergoing TAC. LV function will be determined by echocardiography and hemodynamic studies, fibrosis by picosirious red staining, and flow cytometry, qPCR, western blot and Immunohistochemistry approaches will be used to determine the effect of T cell subsets and their cytokines in cardiac myocyte and fibroblast function. Similar approaches will be used in Aim 3 to translate our findings in Aims 1 and 2 to human biology by exploring the mechanisms regulating human T cell recruitment in HF. Completion of these aims will result in a deeper understanding of how best to regulate T cell mediated inflammation to improve the structural, functional and molecular deficits of the failing heart, and will identify alternative therapeutic approaches to treat HF based on our basic understanding of novel mechanisms that control the timing, type and progression of the T cell immune response in pathological remodeling of the heart.
Inflammation and the improper regulation of the immune response are two key inter-related factors associated with the prognosis of heart failure, a leading cause of hospitalizations and death in the developed world. Attempts at targeting inflammation with anti-inflammatory drugs that inhibit several mechanisms at once, has not been successful. Our pioneering work identifying inflammatory T cells as regulators of inflammation in heart failure, and specific mechanisms regulating their migration to the heart will advance our understanding of this deadly syndrome. The results from this proposal will provide ground for the identification of new therapeutic targets to prevent HF progression.
