FGF21/FGFR1-β-KL Cascade in Cardiomyocytes Modulates Angiogenesis and Inflammation Under Metabolic Stress

Abstract

Diabetes is a metabolic disorder with increased risk of developing heart failure. Inflammation and damaged vasculature are the cardinal features of diabetes-induced cardiac damage. Moreover, systemic metabolic stress triggers discordant intercellular communication, thus culminating to cardiac dysfunction. Fibroblast growth factor 21 (FGF21) is a pleiotropic hormone transducing cellular signals via fibroblast growth factor receptor 1 (FGFR1) and its co-receptor beta-klotho (β-KL). We first demonstrate a decreased expression or activity of FGFR1 and β-KL in both human and mouse diabetic hearts. Reinforcing cardiac FGFR1 and β-KL expression is able to alleviate pro-inflammatory response and vascular damage upon diabetic stress. Using proteomics, we identify the novel cardiomyocyte-derived anti-inflammatory and proangiogenic factors regulated by FGFR1-β-KL activation in diabetes. Although not exhaustive, we provide a unique insight into the protective topology of the cardiac FGFR1-β-KL signalling-mediated intercellular reactions in the heart in response to metabolic stress.

Funding Information: This work was supported by the British Heart Foundation (FS/15/16/31477, FS/18/73/33973, FS/19/70/34650 and PG/19/66/34600 to W. Liu). T.M.A.M. is supported by NIH grants R01HL147921 and P30GM127607, U.S.A. Department of Defense grant W81XWH-20-1-0419 and American Heart Association grant 16SDG29950012. The authors also acknowledge NIH grants F32HL149140 (R.R.E.A.).

Declaration of Interests: TMAM holds equities at Tenaya Therapeutics. The other authors have declared that no conflict of interest exists.

Ethics Approval Statement: Extracts of human myocardial proteins from diabetics and normal subjects were obtained from Asterand (US lab, Hertfordshire, UK). Ethical approval and consent were obtained by Asterand. The Human Tissue Authority of the United Kingdom has approved the use of human tissue extracts. The human serum samples were collected, prepared, and provided by Prof. Handrean Soran, which was approved by the Greater Manchester Research Ethics Committee. The cultured heart protein extracts were a kind gift from Dr. Tamer M.A. Mohamed (University of Louisville). Fresh human heart was provided from a consented and deidentified donor through the USA transplantation network ‘Novabiosis’. The protocol was approved by the IRB committee at the University of Louisville as a non-human subject research. All animal studies were performed in accordance with the United Kingdom Animals (Scientific Procedures) Act 1986 and were approved by the University of Manchester Ethics Committee.

Keywords: metabolic stress, intercellular communication, diabetic cardiomyopathy, inflammation, ANGIOGENESIS