The role of high molecular weight fibroblast growth factor-2 in cardiac response to injury
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Date
2019-12
Authors
Koleini, Navid
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Abstract
Fibroblast growth factor-2 (FGF2) is a multifunctional protein expressed as 18 kDa, low molecular weight (Lo-FGF2), and >20 kDa, high molecular weight (Hi-FGF2) isoforms with potentially distinct biological functions. In the current thesis we have investigated the general hypothesis that the FGF2 isoforms exert distinct long- term effects towards cardiac response to injurious stimuli.
Administration of recombinant Lo- or Hi-FGF2 were equally effective in attenuating acute Doxorubicin (Dox)-induced cardiomyocyte damage and cell death in vitro, through the activation of mTOR/Nrf2/Heme oxygenase-1 pathway. Additionally, it was documented that a non-mitogenic, non-angiogenic mutant form of Lo-FGF2, carrying a serine-to-alanine, S117A, substitution, retained the cardioprotective properties against Dox.
A genetic mouse model lacking endogenous Hi-FGF2 (but not Lo-FGF2) expression, FGF2(Lo) was found to be protected from Dox-induced decline in contractile function, at 10 days post-Dox injection, as assessed by echocardiography, in both male and female mice. Wild type mice showed the expected decline in cardiac function post-Dox. Neutralizing anti-Hi-FGF2 antibodies, furthermore, were able to attenuate Dox-induced damage in cardiomyocytes co-cultured with wild type fibroblasts. Thus, elimination of endogenous Hi-FGF2, or neutralization of secreted, paracrine Hi-FGF2, increases cardiomyocyte resistance to Dox exposure.
Using transverse aortic constriction (TAC) surgery to induced pressure overload it was found that genetic elimination of Hi-FGF2 prevented the decline in systolic function, the increases in cardiac stress markers, and increases in cardiomyocyte size, present in FGF2 (WT) mice at 4-8 weeks post-TAC. In contrast, diastolic dysfunction, fibrosis, and cardiac mass enlargement post-TAC were found to be independent of endogenous Hi-FGF2. Whole cardiac transcriptome analysis revealed increased expression of the cardioprotective heat shock 70 (HSP70) protein in the absence of endogenous Hi-FGF2. In addition, genes involved in modulation of the circadian rhythm, most prominently the nuclear receptor NR1D1, may also contribute to the protected phenotype of the FGF2(Lo) mice, as they were differentially regulated post-TAC depending on the presence or absence of endogenous Hi-FGF2.
Work presented here shows that endogenous Hi-FGF2 aggravates cardiac response to two major causes of heart failure, Dox-toxicity and pressure overload. Neutralization of paracrine Hi-FGF2 through an antibody-based approach is a possible therapeutic approach against these pathologies.
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Keywords
Fibroblast Growth Factor 2, Doxorubicin cardiotoxicity, Pressure overload cardiac injury