Fibroblast growth factors in cardiovascular disease: The emerging role of FGF21

Abstract

Early detection of risk factors for enhanced primary prevention and novel therapies for treating the chronic consequences of cardiovascular disease are of the utmost importance for reducing morbidity. Recently, fibroblast growth factors (FGFs) have been intensively studied as potential new molecules in the prevention and treatment of cardiovascular disease mainly attributable to metabolic effects and angiogenic actions. Members of the endocrine FGF family have been shown to increase metabolic rate, decrease adiposity, and restore glucose homeostasis, suggesting a multiple metabolic role. Serum levels of FGFs have been associated with established cardiovascular risk factors as well as with the severity and extent of coronary artery disease and could be useful for prediction of cardiovascular death. Furthermore, preclinical investigations and clinical trials have tested FGF administration for therapeutic angiogenesis in ischemic vascular disease, demonstrating a potential role in improving angina and limb function. FGF21 has lately emerged as a potent metabolic regulator with multiple effects that ultimately improve the lipoprotein profile. Early studies show that FGF21 is associated with the presence of atherosclerosis and may play a protective role against plaque formation by improving endothelial function. The present review highlights recent investigations suggesting that FGFs, in particular FGF21, may be useful as markers of cardiovascular risk and may also serve as protective/therapeutic agents in cardiovascular disease.

Keywords: angiogenesis; atherosclerosis; biomarker; coronary artery disease; fibroblast growth factor.

Fig. 1.

Left: data from in vitro experiments showing that fibroblast growth factor 21 (FGF21) and peroxisome proliferator-activated receptor-α (PPAR-α) are expressed in rat endothelial cells; incubation of rat endothelial cells with oxidized low-density lipoprotein (Ox-LDL) or bezafibrate induced an upregulation in the expression of FGF21. Human hepatocytes and mouse macrophages increase the LDL uptake as a result of increased LDL receptor (LDLR) expression after stimulation with FGF21; the known effect of statins on hepatocytes is included. Right: results from in vivo findings including a list of metabolic conditions where FGF21 serum levels are documented to be increased and a list of cardiovascular risk factors/indicators positively or negatively correlated with FGF21 serum levels. NAFLD, nonalcoholic fatty liver disease; CAD, coronary artery disease; PAD, peripheral artery disease; HOMA-IR, homeostasis model assessment-estimated insulin resistance; HbA1_c, glycosylated hemoglobin; HDL-C, high-density lipoprotein cholesterol; IMT, intima media thickness; PWV, pulse-wave velocity.

Fig. 2.

Summary of FGF21 physiology in mice and humans. In mice, consumption of a ketogenic diet leads to a PPAR-α-dependent increase of FGF21 in the liver and an increase in serum FGF21 concentrations. FGF21 expression in the liver is also induced by fatty liver disease, obesity, and PPAR-α ligands in mice. PPAR-α ligands, such as fenobibrate, also increase FGF21 messenger RNA expression in human hepatocytes. FGF21 interacts with the FGF receptor (FGFR) in the presence of β-klotho in the mouse liver and adipose tissue. This interaction leads to a PPAR-γ coactivator protein-1α (PGC-1α)-dependent upregulation of fatty acid oxidation and downregulation of lipid synthesis in the liver. In mouse adipose tissue, the presence of PPAR-γ ligands leads to the production of FGF21, and the short-term effect of FGF21 results in a decreased expression of lipolytic genes and leads to lower concentrations of circulating free fatty acids (FFA). FGF21-induced phosphorylation of extracellular signal-regulated kinase-1 (ERK) leads to the activation of glucose transporter-1 (Glut-1) and glucose uptake in mouse 3T3-L1 adipocytes and primary human adipocytes. In humans, serum concentrations of FGF21 are higher in diabetes, obesity, metabolic syndrome, and NAFLD. This effect may be mediated by increased FGF21 liver expression. [From Domouzoglou and Maratos-Flier (15).]

Fig. 3.

Kaplan-Maier curve of combined cardiovascular morbidity and mortality at 24-mo follow-up in patients with type 2 diabetes mellitus according to the level of FGF21 (median value 240.7 pg/ml). Dashed line, patients with FGF21 > 240.7 pg/ml; solid line, patients with FGF21 ≤ 240.7 pg/ml. Log rank test: P = 0.0013. [From Lenart-Lipinska et al. (59).].

Fig. 4.

Cardioprotective action of FGF21 in myocardial ischemia/reperfusion injury. A: immunofluorescence micrographs showing cells undergoing DNA fragmentation in the ischemic myocardium (MI) by the TUNEL assay. Red, cardiac troponin I; green, TUNEL-positive cell nuclei; blue, cell nuclei. Scale bar = 10 mm. B: graphic representation of the fraction of TUNEL-positive cell nuclei in the ischemic myocardium calculated in reference to the total cell nuclei. Means and SDs are presented (n = 8). The P value was estimated by ANOVA among all groups. C: left ventricular slices from wild-type mice and FGF21 2/2 mice with administration of PBS or recombinant FGF21 at 24 h after myocardial ischemia/reperfusion injury, showing the influence of FGF21 on the fraction of acute myocardial infarcts (by the triphenyltetrazolium chloride, TTC, assay) in reference to the area at risk (by the Evans blue assay). Note that the left ventricular wall thickness is thinner in FGF21 2/2 mice with PBS administration than that in wild-type mice and FGF21 2/2 mice with FGF21 administration. Arrows, TTC-positive (red) myocardium within the area at risk. Scale bar = 1 mm. D: graphic representation of the influence of FGF21 on the fraction of acute myocardial infarcts in reference to the area at risk. Means and SDs are presented (n = 8). The P value was estimated by ANOVA among all groups. E: Azan-stained left ventricular sections from wild-type mice and FGF21 2/2 mice with administration of PBS or recombinant FGF21 at 5, 10, and 30 days after myocardial ischemia/reperfusion injury. Red, intact myocardium; blue, myocardial infarcts and fibrous tissue. Scale bar = 1 mm. F: graphic representation of the fraction of myocardial infarcts in wild-type mice (blue) and FGF21 2/2 mice with administration of PBS (red) or recombinant FGF21 (purple) at 5, 10, and 30 days after myocardial injury. Means and SDs are presented. The P value was estimated by ANOVA and is <0.0001 for both time- and treatment-based comparisons. [From Liu et al. (66).]