Abstract
Protection of cardiac microvascular endothelial cells (CMECs) against hypoxia injury is an important therapeutic strategy for treating ischaemic cardiovascular disease. In this study, we investigated the effects of qiliqiangxin (QL) on primary rat CMECs exposed to hypoxia and the underlying mechanisms. Rat CMECs were successfully isolated and passaged to the second generation. CMECs that were pre‐treated with QL (0.5 mg/mL) and/or HIF‐1α siRNA were cultured in a three‐gas hypoxic incubator chamber (5% CO2, 1% O2, 94% N2) for 12 hours. Firstly, we demonstrated that compared with hypoxia group, QL effectively promoted the proliferation while attenuated the apoptosis, improved mitochondrial function and reduced ROS generation in hypoxic CMECs in a HIF‐1α‐dependent manner. Meanwhile, QL also promoted angiogenesis of CMECs via HIF‐1α/VEGF signalling pathway. Moreover, QL improved glucose utilization and metabolism and increased ATP production by up‐regulating HIF‐1α and a series of glycolysis‐relevant enzymes, including glucose transport 1 (GLUT1), hexokinase 2 (HK2), 6‐phosphofructokinase 1 (PFK1), pyruvate kinase M2 (PKM2) and lactate dehydrogenase A (LDHA). Our findings indicate that QL can protect CMECs against hypoxia injury via promoting glycolysis in a HIF‐1α‐dependent manner. Lastly, the results suggested that QL‐dependent enhancement of HIF‐1α protein expression in hypoxic CMECs was associated with the regulation of AMPK/mTOR/HIF‐1α pathway, and we speculated that QL also improved HIF‐1α stabilization through down‐regulating prolyl hydroxylases 3 (PHD3) expression.
Highlights
Wang and Han contributed to this study.Coronary artery disease (CAD) is the most common cardiovascular disease, characterized by insufficient oxygen supply.[1]
The results showed that the decreased ratio of aggregates/monomers in hypoxia group could be reversed by QL treatment, and this beneficial effect was partly abolished by Hypoxia-inducible factor-1a (HIF-1a) Small interfering RNA (siRNA) (Figure 2B)
We explore the protective effects and related mechanisms of QL on hypoxic cardiac microvascular endothelial cells (CMECs) in the absence or presence
Summary
Wang and Han contributed to this study. Coronary artery disease (CAD) is the most common cardiovascular disease, characterized by insufficient oxygen supply.[1]. Protective effects of QL were demonstrated by a multicenter randomized double-blind clinical study including 512 heart failure patients.[19] It was reported that QL could improve cardiomyocyte metabolism and inhibit cardiomyocyte apoptosis.[20,21,22,23] Our previous work found that QL could promote cardiac angiogenesis and up-regulate HIF-1a expression in failing heart and hypoxic CMECs via NRG-1/ErbB-PI3K/Akt/mTOR pathway, promoting cardiac angiogenesis.[24,25] it remains elusive whether QL could improve glucose metabolism in CMECs under hypoxic insult and inhibit CMECs apoptosis via modulating HIF-1a activity and related target genes This study addressed this issue and investigated whether QL could affect glucose metabolism and cell apoptosis in hypoxic CMECs via HIF-1a-dependent mechanisms. We investigated whether QL up-regulates HIF-1a protein expression by regulating post-translationally hydroxylated of HIF-1a or via the AMPK/ mTOR/HIF-1a pathway
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