Long‐term Biological Functions of Fibroblast Growth Factor‐2 (FGF2) in Mouse Hearts Following Myocardial Infarction
Authors: Harris Ronald , Adeyemo Adeola , Redfield Jordan , Huang Chahua , Jiang Min , Ren Xiaoping , Jones Walter Keith , Rubinstein Jack , Schultz Jo El J 
Published: November 2023

Cardiovascular disease is the leading cause of death in men and women; in particular, coronary artery disease or ischemic heart disease, leading to myocardial infarction (MI), affects 1.9 million Americans yearly and makes up more than half of all cardiovascular events in men and women <75 years of age. Prolonged clinical outcomes of acute MI are: cardiac remodeling (muscle hypertrophy, lumenal dilation, and scar formation), cardiac dysfunction, arrhythmias, and re‐infarction. Current treatments include: lifestyle changes, drugs such as cholesterol‐modifying medications or surgical procedures including coronary artery bypass surgery or angioplasty. A new “drug” field, known as therapeutic revascularization, is emerging which uses growth factors, including fibroblast growth factors, to help treat coronary artery disease. FGF2 is composed of different protein isoforms, low molecular weight (LMW) localized to the cytosol and nucleus or high molecular weight (HMW) found in nucleus, that are translated from the Fgf2 gene, and is implicated in many processes including cell survival, angiogenesis, and cell growth. Our previous research demonstrates that FGF2 can acutely protect the heart during an ischemic event, by reducing cardiomyocyte death (involves the LMW and HMW FGF2) and improving cardiac function (linked to LMW FGF2). Yet, the question remains as to the long‐term biological actions of FGF2 following a heart attack; in particular, the effects of the individual FGF2 isoforms in ischemia‐induced cardiac remodeling, dysfunction, and revascularization. To test this, wildtype (WT) mice (containing all FGF2 isoforms), mice with no FGF2 (Fgf2KO), mice expressing only LMW isoform (HMWKO), and mice expressing only HMW isoforms (LMWKO) were subjected to no ischemia or 60 minutes of ischemia followed by 6 weeks of reperfusion. Echocardiography was performed at baseline and specific times of reperfusion to assess changes in left ventricular (LV) mass (measure of cardiac remodeling) and cardiac function. Revascularization of the heart following an MI was assessed via immunohistological techniques using a cell marker for vascular smooth muscle cells (primary antibody for alpha‐smooth muscle actin) or endothelial cells (primary antibody for GSI lectin) to differentiate large vessels (arterioles/venules) from capillaries, respectively. Mice expressing all FGF2 isoforms (WT) had worse cardiac function following MI. Mice expressing all FGF2 isoforms (WT) as well as mice only expressing the LMW isoform (HMWKO) had increased LV mass. Angiogenesis (capillary levels) was elevated in mice expressing all FGF2 isoforms (WT), but no increase in larger vessel density was observed following MI in any of the genotypes. The findings suggest that the FGF2 isoforms have differential roles in the long‐term “clinical outcomes” following an acute MI.

Support or Funding Information

RJH was supported as a Dalton Zannoni Fellow of the American Society of Pharmacology and Experimental Therapeutics (ASPET) with funds generously provided by ASPET and the University of Cincinnati. This work was supported by AHA 14GRNT20450150 (JJS) and NIH R01 HL075633 (JJS).