Doctor of Philosophy (PHD)
Molecular Cell and Developmental Biology (Medicine)
Date of Defense
First Committee Member
Second Committee Member
Third Committee Member
Fourth Committee Member
Diabetic cardiomyopathy is a diabetes-associated cardiovascular disease (CVD), which causes heart dysfunction. Left ventricular hypertrophy (LVH) is a key feature of diabetic cardiomyopathy. Molecular mechanisms underlying this condition are largely unknown. Fibroblast growth factor (FGF) 21, an adipokine that regulates metabolism, has been found to be elevated in the circulation of type 2 diabetic patients. This thesis evaluates the long-term effects of increased serum FGF21 levels on the heart. It reveals that FGF21 induces hypertrophy of cardiac myocytes via FGF receptor (FGFR) 4-dependent activation of the pathological and pro-hypertrophic PLCγ/calcineurin/NFAT pathway, but independently of β-klotho, the canonical co-receptor for FGF21 in the liver. FGF21 transgenic mice develop LVH at 6 months of age. 6 weeks of pan-FGFR inhibitor treatment of diabetic ob/ob mice or 24 weeks of FGFR4 specific blockade of diabetic db/db mice inhibits pathological cardiac signaling and LVH development. These results show that FGF21 can induce hypertrophic signaling in the heart independently of β-klotho, that long-term FGF21 elevation may be responsible for the development of diabetic cardiomyopathy, and that FGFR4 blockade might serve as a novel cardio-protective therapy in diabetic patients.
Endocrine Fibroblast Growth Factors; Cardiac Hypertrophy; Diabetic Cardiomyopathy; Hypertrophic Signaling
Schramm, Karla, "Fibroblast Growth Factor 21 Induces Cardiac Hypertrophy" (2017). Open Access Dissertations. 1965.
Available for download on Friday, September 06, 2019