The Role of FGF Signaling in the Regulation of Adult Murine Cardiomyocyte Contractility and Pathologic Hypertrophy

Cardiovascular diseases (CVDs ) have been the leading cause of death in the United States for decades. They cause significant strain on the heart, resulting in an ongoing remodeling process that initially maintains cardiac function, but ultimately becomes maladaptive. The signaling pathways that drive cardiac remodeling are extremely complex and poorly understood, and therefore, a better understanding of the mechanisms involved in the development and progression of CVDs is essential in order to diagnose and treat these diseases more effectively. Fibroblast growth factors (FGFs) and their receptors are part of a large family of highly conserved signaling molecules that have been implicated in postnatal cardiac remodeling. FGF signaling increases following injury to the heart, and published studies demonstrate that FGF2 is cardioprotective following cardiac stress or injury. Despite the importance of FGF2 following injury, mice that lack or overexpress FGF2 develop normally and do not have any cardiac phenotype under homeostatic conditions. It is currently unknown how FGF signaling is regulated in the adult heart and why effects of FGF2 are only observed following injury. As a result, it was the goal of my thesis research to gain a better understanding of the role of FGF signaling in adult cardiac remodeling. I hypothesized that FGF signaling may be repressed in the adult heart under homeostatic conditions and becomes reactivated following injury. I utilized a doxycycline-inducible, cardiomyocyte-specific, constitutively-active FGF receptor (caFGFR1) mouse model to test whether the cardiomyocyte has the capacity to respond to a cell autonomous FGF signal. Induction of this transgene led to immediate changes in cardiac contractility and the eventual development of hypertrophic cardiomyopathy (HCM) without progression to heart failure or premature death. Induction of caFGFR1 appears to increase the calcium sensitivity and decrease relaxation of the sarcomere through dephosphorylation of troponin I, and also by potentially increasing cytosolic calcium, mechanisms implicated in classic HCM models. Our doxycycline-inducible cardiomyocyte-specific caFGFR1 mouse provides a unique model of HCM that can be utilized to further characterize pathways that lead to phenotype development, as well as prevention or reversal