In this study, TAC induced HF model were constructed in SD rats, and FGF21nAb knockdown and rmFGF21 overexpression were used to verify whether FGF21 could improve ventricular remodeling in HF rats and thereby improve cardiac function. The conclusions are as follows: (1) FGF21 improves cardiac function in TAC-induced HF rats; (2) FGF21 improves TAC-induced ventricular remodeling in HF rats.
Firstly, we validated the model with echocardiography and serological indicators. We found that LVEF and LVFS significantly decreased, along with BNP significantly increased in TAC induced HF model. Similar to the results reported in the literature, the heart function of rats with heart failure was significantly reduced, accompanied by cardiomyopathic hypertrophy [17, 18]. At the same time, we also noted that echocardiography and serological indicators were further deteriorated after FGF21nAb injection, suggesting that FGF21 may play a protective role in the development of HF. Then, we used rmFGF21 to significantly improve cardiac echocardiography and serological indexes after overexpression of FGF21 in HF models, suggesting a significant improvement in cardiac function, and further verified the cardiac protective effect of FGF21 in HF. This is consistent with the conclusions reported in the literature, which found that FGF21 can improve the function of failing heart by increasing LVEF and LVFS and decreasing serum BNP levels [19, 20].
Pathological ventricular remodeling, characterized by increased interstitial fibrosis, loss of cardiomyocytes, and increased collagen, is a critical period in the development of heart failure. Planavila et al. [21] studied the role of FGF21 in the heart and found that compared with wild-type mice, the heart mass, myocardial cross-section area, diastolic septal thickness, end-diastolic and end-systolic diameter of FGF21 gene knockout mice treated with isoproterenol significantly increased, while the left ventricular ejection fraction significantly decreased. Exogenous administration of recombinant FGF21 protein can partially reverse or alleviate these pathological changes, suggesting that FGF21 has anti-inflammatory and inhibitory effects on myocardial hypertrophy. Our study is similar to the above conclusions, heart mass increase, inflammatory cell infiltration, myocardial hypertrophy marker Myh7 and inflammatory marker IL-1β increase significantly in heart failure rats, rmFGF21 can improve the above phenomena.
Myocardial fibrosis is a crosslinking process of collagen fiber deposition and extracellular matrix (ECM), which is an important feature of ventricular remodeling, can cause ventricular wall stiffness, cardiac structure and function changes, and eventually lead to refractory heart failure, arrhythmia, and even sudden death [22–24]. In this study, it was found that a large amount of collagen fiber deposition in the interstitial and peritubular rats and TGFβ levels in serum and tissue were significantly increased in rats with heart failure, while rmFGF21 reduced the fiber deposition in peritubular and interstitial and decreased the levels of TGFβ in serum and myocardial tissue, thereby inhibiting myocardial fibrosis. Consistent with the conclusions reported in the literature, studies have found that FGF21 can alleviate myocardial fibrosis in acute myocardial infarction, diabetic cardiomyopathy, and hypertensive heart disease, and reduce the biomarkers of fibrosis [25–27].
Cardiomyocyte apoptosis is closely related to cardiac remodeling, and apoptosis has been found in the myocardium of hypertensive cardiac hypertrophy and dilated cardiomyopathy [28, 29]. Studies have shown that FGF21 significantly inhibits early diabetes-induced cardiomyocyte apoptosis by activating the ERK1/2 signaling pathway. This study also found that exogenous administration of FGF21 could significantly inhibit cardiac dysfunction, myocardial fibrosis and ventricular remodeling caused by late diabetes, thereby preventing the occurrence and development of diabetic cardiomyopathy [30]. In this study, it was found that the level of bcl-2 in myocardial tissue of rats with heart failure were significantly decreased, and bax were significantly increased. While rmFGF21 increased the level of bcl-2 and decreased the level of bax in myocardial tissue, thus playing an anti-apoptotic role.
Oxidative stress refers to the imbalance of oxidation and antioxidant effects in the body, resulting in a large number of oxidative intermediates such as ROS, thus destroying the heart structure and myocardial contractility, and making the body more prone to heart failure [31]. High ROS levels can stimulate increased FGF21 expression levels, then FGF21 could reduce oxidative stress by upregulating mitochondrial uncoupling protein 3 and superoxide dismutase 2 [32, 33]. The above studies suggest that elevated FGF21 may be to resist oxidative stress and reduce the damage of ROS to cardiac structure, thus playing a cardioprotective role, which is consistent with our conclusions. This study found that ROS levels in heart failure rats were significantly increased, and rmFGF21 reduced ROS levels in myocardial tissue, thereby alleviating oxidative stress in HF rats.
The normal function of the heart requires extremely high energy, consuming more ATP per gram of tissue than any other organ in the body. It is essential to maintain the normal production of adenosine triphosphate for the maintenance of the normal physiological function of the heart. In a failing heart, energy metabolism is disturbed and mitochondrial function and oxidative metabolism are impaired [34]. On the other hand, mitochondrial abnormalities can significantly reduce oxygen utilization and exercise tolerance in patients with heart failure [35]. Studies have found that FGF21 can improve cardiometabolic regulation by activating signaling pathways such as fatty acid β oxidation in heart mitochondria, thus playing a cardioprotective role [36]. Therefore, we wanted to evaluate whether FGF21 could improve the energy metabolism of myocardial mitochondria. The results showed that ATP content in the myocardium of HF rats was significantly decreased, and overexpression of FGF21 could significantly increase ATP content in the myocardium of HF rats.