Diabetic cardiomyopathy is a complex entity associated with multiple contributing mechanisms and consequent manifestations in the clinic. Emerging evidence implicates that increased activity of fibroblast growth factor receptor 1 (FGFR1) is required during induced cardiac damage and remodeling. However, little is known about the roles of FGFR1 on diabetic cardiomyopathy (DCM). We hypothesized that the high-concentration glucose (HG)/diabetes induced cardiac pathophysiological and malfunctional alterations are linked to the activation of FGFR1. We tested this hypothesis by challenging cultured cardiomyocytes with high-concentration glucose and myocardium of streptozotocin (STZ)-induced type 1 diabetic mice (T1D). This study indicated that FGFR1 phosphorylation was increased in myocardium of streptozotocin (STZ)-induced type 1 diabetic mice (T1D) and cultured cardiomyocytes to high-concentration glucose. The inactivation of FGFR1 by selective inhibitors AZD4547, neutralized the increased FGFR1 phosphorylation and significantly reduced myocardial structural and functional deficits in type 1 diabetic mice. In vitro, overexpression of FGFR1 by lentivirus-transfection aggravated HG-induced fibrosis and hypertrophy in cardiomyocytes. Blocking FGFR1 by AZD4547 or CRISPER-Cas9 knockout, HG-induced fibrosis and hypertrophy in cardiomyocytes were significantly decreased. Then, GSEA analysis of RNA-sequencing implied that collagen5a1(Col5a1) and periostin (Postn) were associated with fibrosis and myosin heavy chain 4/7/8/9 (Myh4/7/8/9) were associated with hypertrophy. Analysis by PASTAA database and confirmatory tests by inhibiting FGFR1 or MAPKs indicated that MAPKs/AP-1 plays a crucial role in FGkFR1-mediated cardiomyocyte injuries challenged by HG. These results reveal an unrecognized FGFR1/MAPKs/AP-1 signaling axis involved in the development and progression of DCM and suggest that AZD4547 might be a potential agent for treating DCM.

Disclosure

X. Chen: None. Y. Wang: None. F. Shen: None.

Funding

National Natural Science Foundation of China (81700335)

Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. More information is available at http://www.diabetesjournals.org/content/license.