Abstract 382: Cell Type-specific Fibroblast Growth Factor Receptors That are Regulated in Human Heart Disease

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Chronic kidney disease (CKD) is characterized by increased serum levels of the phosphaturic hormone fibroblast growth factor 23 (FGF23), the development of left ventricular hypertrophy, and increased risk of mortality due to cardiovascular disease. The FGF receptors (FGFRs) responsible for facilitating the effect of FGF23 on the heart and the expression patterns of FGFRs in the different cell types in the heart remain largely uncharacterized. We hypothesized that cardiomyocytes express a different FGFR profile than cardiac fibroblasts and that this differential expression profile could contribute to cell type-specific responses to FGF23. We measured FGFR mRNA levels at baseline and following pro-hypertrophic growth factor stimulation in isolated adult rat ventricular cardiomyocytes (ARVMs), neonatal rat ventricular cardiomyocytes (NRVMs), and neonatal rat ventricular fibroblasts (NRVFs). At baseline, NRVMs expressed predominantly FGFR1 but also expressed FGFRs 2 and 3. In ARVMs, FGFRs 1 and 3 predominated while FGFRs 2 and 4 were expressed at very low levels. FGFRs in ARVMs and NRVMs were unchanged by growthfactor stimulation. At baseline, NRVFs expressed equal amounts of FGFRs 1, 2 and 3 which were all downregulated with FGF23 stimulation. To determine whether these results translated to human hearts, we examined the FGFR profile in a cohort of non-failing, hypertrophic cardiomyopathy (HCM), and ischemic cardiomyopathy (ICM) human patient samples. Compared to non-failing patients, we found FGFR2 was significantly increased in HCM patients and trended towards an increase in ICM patients. The cardiac FGFR2 profile matched the FGF23 profile. In addition, we found that FGFR4 was significantly down regulated in both ICM and HCM compared to non-failing patients. In conclusion, different cell types in the heart differ in their FGFR profiles at baseline. The FGFR profile does not change in NRVMs or ARVMs in response to FGF23 treatment, but the expression of FGFRs 1, 2, and 3 decrease in NRVFs in response to FGF23. HCM and ICM in humans is characterized by an increase in FGFR2 and FGF23 expression accompanied with a downregulation of FGFR4 expression. Modulating FGFRs in the myocardium may provide a novel therapeutic target in CKD patients.