Gualou-Xiebai-Banxia Decoction Enhances Cardiac FGF21 Sensitivity through βKlotho Upregulation in T2DM Complicated with CHD Rats

Introduction: A renowned traditional Chinese medicine (TCM) classical formula, Gualou-Xiebai-Banxia decoction (GXBD), exhibits unique and significant therapeutic effects in patients with diabetes mellitus complicated by coronary heart disease (DM-CHD). The mechanism underlying its clinical efficacy remains poorly defined. GXBD exerts a potent dual capacity to ameliorate glycolipid metabolic disorders while mitigating MI-induced myocardial injury. This synergistic effect is very similar to the beneficial effects exerted by fibroblast growth factor 21 (FGF21). This study aims to investigate whether GXBD prevents T2DM-CHD from inflicting heart damage and glycolipid metabolic disorders by activating the FGF21/FGF receptor 1 (FGFR1)/βKlotho/fibroblast receptor substrate 2α (FRS2α) pathway. Methods: To establish the T2DM-CHD model, SD rat was intraperitoneally injected with streptozocin after high-fat emulsion gavage for twenty-eight days. Then, the coronary artery ligation operation was performed. GXBD was administered intragastrically. Plasma levels of FGF21, myocardial enzymes, blood glucose, and lipid were detected by enzyme-linked immunosorbent assay. Myocardial ischemic size was assessed via triphenyltetrazolium chloride staining, while protein and mRNA expression were analyzed by immunofluorescence, Western blot, and RTPCR. Results: GXBD treatment significantly alleviated myocardial injury and glycolipid metabolic disorders, while reducing circulating and cardiac FGF21 levels in T2DM-CHD rats. Notably, this classical TCM prescription markedly upregulated cardiac βKlotho and Klb mRNA expression, and enhanced the expression and phosphorylation of FRS2α in model rats. Discussion: In the diabetic heart, AMI fails to effectively activate the FGF21-FRS2α signaling pathway due to insufficient βKlotho upregulation, while GXBD restores FGF21 sensitivity by inducing βKlotho expression, thereby exerting cardioprotective effects. Conclusions: In the diabetic heart, AMI fails to effectively activate the FGF21-FRS2α signaling pathway due to insufficient βKlotho upregulation, while GXBD restores FGF21 sensitivity by inducing βKlotho expression, thereby exerting cardioprotective effects. These findings elucidated a key pathological mechanism in T2DM-CHD and provide mechanistic insights into GXBD's therapeutic efficacy.