Cao Yiqiu, Dong Zhu, Yang Dongpeng, Ma Ximiao, Wang Xiaowu
Department of cardiac surgery, Hainan General Hospital, Hainan Affiliated Hospital of Hainan Medical University, Haikou 570311, Hainan, PR China; The First School of Clinical Medicine, Southern Medical University, Guangzhou 510515, Guangdong, PR China.
The First School of Clinical Medicine, Southern Medical University, Guangzhou 510515, Guangdong, PR China; Department of Cardiovascular surgery, Zhujiang Hospital, Southern Medical University, Guangzhou 510280, Guangdong, PR China.
Chem Phys Lipids. 2021 Nov;241:105138. doi: 10.1016/j.chemphyslip.2021.105138. Epub 2021 Sep 20.
Diabetes mellitus ranks as a major risk cause for disability and death around the world due to its complications, especially diabetic cardiomyopathy (DCM). Glucolipotoxicity is one of the critical causal factors of DCM. Recent finding confirms the beneficial roles of Z-ligustilide in diabetes mellitus. Nevertheless, its efficacy in DCM remains elusive. Here, Z-ligustilide elevated high glucose/high palmitic acid (HG/P)-inhibited cell viability and attenuated HG/P-induced cell apoptosis, caspase-3 activity, pro-apoptotic Bax and anti-apoptotic Bcl-2 protein expression. Furthermore, Z-ligustilide alleviated HG/P-evoked oxidative damage by decreasing HG/P-induced elevation in ROS, lactate dehydrogenase (LDH) and malondialdehyde (MDA) leakage, but increasing antioxidant enzyme-superoxide dismutase (SOD) and glutathione (GSH) levels suppressed by HG/P. Concomitantly, Z-ligustilide attenuated HG/P-induced cardiomyocyte fibrosis by increasing MMP-14 expression and diminishing HG/P-enhanced fibrotic protein expression, including collagen I, collagen II and TGF-β. Mechanistically, Z-ligustilide offset the adverse effects of HG/P on the activation of the AMPK/GSK-3β/Nrf2 pathway. Importantly, blocking the AMPK signaling overturned the protective efficacy of Z-ligustilide against HG/P-induced cardiomyocyte oxidative damage, inflammation and fibrosis. Together, these findings highlight that Z-ligustilide may alleviate glucolipotoxicity-induced cardiomyocyte dysfunction by regulating cell oxidative injury, inflammation and fibrosis via the AMPK/GSK-3β/Nrf2 pathway. Consequently, Z-ligustilide may represent a promising therapeutic agent against DCM by restoring cardiomyocyte dysfunction.
由于糖尿病的并发症，尤其是糖尿病性心肌病（DCM），糖尿病在全球范围内是导致残疾和死亡的主要风险因素。糖脂毒性是DCM的关键致病因素之一。最近的研究证实了Z-藁本内酯在糖尿病中的有益作用。然而，其在DCM中的疗效仍不明确。在此，Z-藁本内酯提高了高糖/高棕榈酸（HG/P）抑制的细胞活力，并减轻了HG/P诱导的细胞凋亡、半胱天冬酶-3活性、促凋亡蛋白Bax和抗凋亡蛋白Bcl-2的表达。此外，Z-藁本内酯通过降低HG/P诱导的活性氧（ROS）、乳酸脱氢酶（LDH）和丙二醛（MDA）泄漏的升高来减轻HG/P引起的氧化损伤，但增加了被HG/P抑制的抗氧化酶超氧化物歧化酶（SOD）和谷胱甘肽（GSH）水平。同时，Z-藁本内酯通过增加基质金属蛋白酶-14（MMP-14）的表达并减少HG/P增强的纤维化蛋白表达，包括I型胶原蛋白、II型胶原蛋白和转化生长因子-β（TGF-β），从而减轻HG/P诱导的心肌细胞纤维化。从机制上讲，Z-藁本内酯抵消了HG/P对AMPK/GSK-3β/Nrf2信号通路激活的不利影响。重要的是，阻断AMPK信号通路推翻了Z-藁本内酯对HG/P诱导的心肌细胞氧化损伤、炎症和纤维化的保护作用。总之，这些发现表明Z-藁本内酯可能通过AMPK/GSK-3β/Nrf2信号通路调节细胞氧化损伤、炎症和纤维化，从而减轻糖脂毒性诱导的心肌细胞功能障碍。因此，Z-藁本内酯可能是一种通过恢复心肌细胞功能障碍来治疗DCM的有前途的治疗药物。
