Department of Cardiology, Sir Run Run Shaw Hospital, College of Medicine, Zhejiang University, Hangzhou, Zhejiang Province, PR China.
Key Laboratory of Cardiovascular Intervention and Regenerative Medicine of Zhejiang Province, Hangzhou, Zhejiang Province, PR China.
Cell Biol Int. 2021 Jul;45(7):1393-1403. doi: 10.1002/cbin.11573. Epub 2021 Apr 23.
Farnesyl pyrophosphate synthase (FPPS)-catalyzed isoprenoid intermediates are involved in diabetic cardiomyopathy. This study investigated the specific role of FPPS in the development of diabetic cardiomyopathy. We demonstrated that FPPS expression was elevated in both in vivo and in vitro models of diabetic cardiomyopathy. FPPS inhibition decreased the expression of proteins related to cardiac fibrosis and cardiomyocytic hypertrophy, including collagen I, collagen III, connective tissue growth factor, natriuretic factor, brain natriuretic peptide, and β-myosin heavy chain. Furthermore, FPPS inhibition and knockdown prevented phosphorylated c-Jun N-terminal kinase 1/2 (JNK1/2) activation in vitro. In addition, a JNK1/2 inhibitor downregulated high-glucose-induced responses to diabetic cardiomyopathy. Finally, immunofluorescence revealed that cardiomyocytic size was elevated by high glucose and was decreased by zoledronate, small-interfering farnesyl pyrophosphate synthase (siFPPS), and a JNK1/2 inhibitor. Taken together, our findings indicate that FPPS and JNK1/2 may be part of a signaling pathway that plays an important role in diabetic cardiomyopathy.
法呢基焦磷酸合酶（FPPS）催化的类异戊二烯中间体参与糖尿病心肌病的发生。本研究探讨了 FPPS 在糖尿病心肌病发展中的特定作用。我们证明，FPPS 在糖尿病心肌病的体内和体外模型中表达均升高。FPPS 抑制降低了与心肌纤维化和心肌细胞肥大相关的蛋白的表达，包括胶原 I、胶原 III、结缔组织生长因子、利钠肽、脑利钠肽和β-肌球蛋白重链。此外，FPPS 抑制和敲低可防止体外磷酸化 c-Jun N 末端激酶 1/2（JNK1/2）的激活。此外，JNK1/2 抑制剂可下调高葡萄糖诱导的糖尿病心肌病反应。最后，免疫荧光显示，高葡萄糖可增加心肌细胞的大小，而唑来膦酸盐、小干扰法呢基焦磷酸合酶（siFPPS）和 JNK1/2 抑制剂可降低心肌细胞的大小。综上所述，我们的研究结果表明，FPPS 和 JNK1/2 可能是参与糖尿病心肌病的信号通路的一部分，在其中发挥重要作用。
