Fibroblast growth factor 21 protects against pathological cardiac remodeling by modulating galectin‐3 expression

Abstract

Background/Aims: Fibroblast growth factor 21 (FGF21) plays a protective role in ischemia/reperfusion induced cardiac injury. However, the exact molecular mechanism of FGF21 action remains unclear. This study was designed the protective effect of FGF21 on the heart and its mechanism.Method: Adenovirus vector expressing FGF21 or control β-galactosidase was injected into the myocardium of mice. Myocardial injury was observed by tissue staining and immunohistochemical staining. The expression level of caspases-3 and galectin-3 in myocardial cells were observed by immunoblotting. Then, hypoxia-induced cell model was established. Small interfering RNA (SiRNA) and plasmid were transfected into H9c2 using Lipofectamine 2000 reagent (Invitrogen). The expression levels of galectin-3, ECM and cystatin-3 in cells were observed by immunoblotting, and the relationship between fibroblast growth factor 21 and galectin-3 was analyzed. Result: Cell test in vitro showed that FGF21 could inhibit apoptosis and decrease the expression of ECM (ColIaI, fibronectin, and alpha-SMA) under hypoxia. Western blot data showed that hypoxia-induced cell damage increased galectin-3 levels, while FGF21 decreased galactose lectin-3 levels. In addition, inhibition of galactose agglutinin-3 expression by siRNA enhanced the cardioprotective effect of FGF21, while overexpression of galectin-3 reduced the cardioprotective effect of fibroblast growth factor 21.Conclusion: FGF21 may be a novel therapy for hypoxia-induced cardiac injury by regulating the expression of galectin-3. K E Y W O R D Sbiomarkers, cardioprotection, fibroblast growth factor-21, galectin-3

FGF21-FGFR4 signaling in cardiac myocytes promotes concentric cardiac hypertrophy in mouse models of diabetes

“…Presumably via different downstream effectors that regulate myocyte apoptosis, MEK1 transgenic mice and ERK2 hemizygous knock-out mice exhibit decreased and increased infarct size, respectively, after ischemia-reperfusion (Lips et al, 2004). Likewise, gain and loss of ERK1/2 signaling may explain the beneficial and deleterious effects on myocyte survival and infarct size of exogenous FGF21 and Fgf21 knock-out, respectively, in mice subjected to ischemia-reperfusion injury or permanent coronary artery ligation (Joki et al, 2015;Liu et al, 2013), although other ERK1/2-independent pathways may also be involved (Hu et al, 2018;Li et al, 2020b;Sun et al, 2019). This pro-survival signaling could complicate the targeting of FGF21-FGFR4 signaling in diabetic cardiomyopathy.…”

“…Notably, FGF21 expression has been found to be increased in HFpEF patients with diastolic dysfunction (Chou et al, 2016). FGF21 appears to have direct effects on the heart, including cardio-protective actions of short-term FGF21 elevations during ischemia/reperfusion injury, β-adrenergic activation, or hypertension (Hu et al, 2018;Joki et al, 2015;Li et al, 2020b;Li et al, 2019;Liu et al, 2013;Patel et al, 2014;Planavila et al, 2013;Planavila et al, 2015a;Ruan et al, 2018;Sun et al, 2019).…”

Mechanism of fibroblast growth factor 21 in cardiac remodeling

“…It can promote macrophage migration, cardiac fibroblast proliferation, and collagen deposition in the matrix, leading to reduced ejection fraction ( 104 ). FGF21 regulated Gal-3 levels in H9c2 cells in a dose-dependent manner and ECM-related proteins (fibronectin, collagen I) levels were also decreased under FGF21 treatment ( 105 ). This suggested that FGF21 may play a protective role in the heart by reducing the level of cardiac fibrosis through downregulating Gal-3 levels.…”

Targeting FGF21 in cardiovascular and metabolic diseases: from mechanism to medicine

“…In the H9c2 hypoxia/reoxygenation model, FGF21 can improve H9c2 cell I/R injury by promoting autophagy via different pathways, such as the FGF21-Beclin‑1/vacuolar protein sorting 34 proteins-autophagy pathway 73 and the FGF21-microRNA-145- autophagy pathway 72 . FGF21 can also decrease the expression levels of galectin-3 to alleviate hypoxia-induced cardiac myocyte injury in vivo 74 . In addition, FGF21 can improve the energy metabolism of H9c2 cells after I/R via the FGF21-angiopoietin-2-glucose transporter 1 pathway in vitro 75 .…”