Alleviation of glucolipotoxicity-incurred cardiomyocyte dysfunction by Z-ligustilide involves in the suppression of oxidative insult, inflammation and fibrosis.
Chemistry and physics of lipids(2021)
Abstract
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.
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Key words
Diabetic cardiomyopathy,Glucolipotoxicity,Z-ligustilide,Cardiomyocyte,AMPK signaling
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