ACTIVATION OF CARDIAC FGFR4 CAUSES LEFT VENTRICULAR HYPERTROPHY

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 DESCRIPTION (provided by applicant): Chronic kidney disease (CKD) is a health epidemic that increases risk of death due to cardiovascular disease. By promoting heart failure, cardiac hypertrophy is an important pathology in CKD and affects up to 90% of patients by the time they reach dialysis. Fibroblast growth factor 23 (FGF23) is a bone-secreted hormone that regulates phosphate homeostasis. Serum FGF23 levels are constitutively elevated in CKD and continuously rise as patient's progress to renal failure. While this massive increase in FGF23 helps to maintain normal serum phosphate levels, prospective human studies demonstrated a dose-dependent association between higher FGF23 levels and greater risks of cardiovascular events and mortality. As a potential mechanism, we demonstrated that elevated FGF23 is strongly associated with cardiac hypertrophy in a large CKD cohort, and that FGF23 can induce hypertrophy in cultured cardiac myocytes and in a series of animal models with elevated serum FGF23. Our previous work suggests that FGF23 excess represents a novel, risk-multiplying mechanism of pathological cardiac hypertrophy in CKD. The purpose of this proposal is to identify the FGF23 receptor that is required for cardiac remodeling in CKD and the underlying signal mechanism in cardiac myocytes. Our preliminary data in heterologous cell cultures indicate that of the four FGF receptor isoforms (FGFR1-4), FGF23 can specifically activate FGFR4 which results in the activation of phospholipase C (PLC). Blockade of PLC, calcineurin or FGFR4 inhibits FGF23-induced hypertrophic growth of cardiac myocytes in vitro. Different from wild type mice, elevating FGF23 in global FGFR4 knock-out mice by high phosphate diet does not because cardiac hypertrophy, and isolated cardiac myocytes from these mice are protected from FGF23-mediated hypertrophy. In Aim 1 we will determine if FGFR4 activation is sufficient to induce cardiac hypertrophy. Our preliminary data indicate that an established knock-in mouse model with an FGFR4 gain-of- function mutation (FGFR4-G385R) has hypertrophy at 6-months of age, and we will analyze if these mice develop further cardiac injury including myocyte apoptosis and interstitial fibrosis leading to heart failure. Furthermore, we will analyze if cardiac remodeling in FGFR4-G385R mice is exacerbated in response to pressure overload or neuroendocrine stimulation. In Aim 2 we want to study the mechanism of FGF23-FGFR4 mediated hypertrophy. We postulate that FGFR4 activation induces calcineurin/NFAT signaling in cardiac myocytes. In Aim 3 we will analyze if FGFR4 is required for pathological cardiac remodeling in animals with prolonged FGF23 elevations. In a proof-of-concept experiment we want to determine if a highly specific FGFR4 blocking antibody attenuates hypertrophy in a rodent model of CKD. FGFR4 blockade might serve as a novel therapeutic strategy to prevent or treat heart failure in CKD, and potentially more generally in patients with other forms of cardiovascular disease.