Key result
FGFR1 inhibition prevents diabetes-induced cardiac inflammation, fibrosis, and dysfunction in mice.
Why the study?
To identify new receptor tyrosine kinase targets driving the development of diabetic cardiomyopathy.
Does FGFR1 inhibition prevent cardiac inflammation and preserve cardiac function in diabetic cardiomyopathy models?
Does FGFR1 inhibition prevent cardiac inflammation and preserve cardiac function in diabetic cardiomyopathy models?
FGFR1 activation via the TLR4/c-Src pathway drives diabetic cardiomyopathy, and its inhibition prevents cardiac inflammation and dysfunction in diabetic mice.
FGFR1 inhibition may attenuate diabetic cardiomyopathy in mice; leaves open clinical translation.
Protein tyrosine kinases (RTKs) modulate a wide range of pathophysiological events in several non-malignant disorders, including diabetic complications. To find new targets driving the development of diabetic cardiomyopathy (DCM), we profiled an RTKs phosphorylation array in diabetic mouse hearts and identified increased phosphorylated fibroblast growth factor receptor 1 (p-FGFR1) levels in cardiomyocytes, indicating that FGFR1 may contribute to the pathogenesis of DCM. Using primary cardiomyocytes and H9C2 cell lines, we discovered that high-concentration glucose (HG) transactivates FGFR1 kinase domain through toll-like receptor 4 (TLR4) and c-Src, independent of FGF ligands. Knocking down the levels of either TLR4 or c-Src prevents HG-activated FGFR1 in cardiomyocytes. RNA-sequencing analysis indicates that the elevated FGFR1 activity induces pro-inflammatory responses via MAPKs–NFκB signaling pathway in HG-challenged cardiomyocytes, which further results in fibrosis and hypertrophy. We then generated cardiomyocyte-specific FGFR1 knockout mice and showed that a lack of FGFR1 in cardiomyocytes prevents diabetes-induced cardiac inflammation and preserves cardiac function in mice. Pharmacological inhibition of FGFR1 by a selective inhibitor, AZD4547, also prevents cardiac inflammation, fibrosis, and dysfunction in both type 1 and type 2 diabetic mice. These studies have identified FGFR1 as a new player in driving DCM and support further testing of FGFR1 inhibitors for possible cardioprotective benefits.
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Chen et al. (2024) studied Diabetic cardiomyopathy. Cardiomyocyte-specific FGFR1 knockout or AZD4547 (FGFR1 inhibitor) was evaluated on Cardiac inflammation, fibrosis, and dysfunction. Pharmacological inhibition of FGFR1 by AZD4547 or cardiomyocyte-specific FGFR1 knockout prevents diabetes-induced cardiac inflammation, fibrosis, and dysfunction in mice.
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