ox-LDL induces coronary microvascular dysfunction via endoplasmic reticulum stress in HCMECs: the protection of propionate

Abstract

Abstract Coronary microvascular dysfunction (CMD) is an important pathogenesis of various cardiovascular diseases. Lower endothelial nitric oxide synthase (eNOS) phosphorylation leads to reduced endothelium-derived relaxing factor nitric oxide (NO) generation, causing and accelerating CMD. Endoplasmic reticulum stress (ER stress) has been shown to reduce NO production in umbilical vein endothelial cells. Oxidized low-density lipoprotein (ox-LDL) damages endothelial cell function. But the relationship between ox-LDL and coronary microcirculation has not been assessed. Short-chain fatty acid (SCFA) is fermentation products of the gut microbiome, could improve endothelial-dependent vasodilation in human adipose arterioles, the effect of SCFA on coronary microcirculation is unclear. In this study, we found ox-LDL stimulated expression of ER chaperone GRP78, and further activated downstream PERK/eIF2a, IRE1/ JNK and ATF6 signaling pathways, resulting in a decrease in eNOS phosphorylation and NO production in human cardiac microvascular endothelial. Furthermore, SCFA-propionate can inhibit ox-LDL-induced eNOS phosphorylation reduction, raise NO production, the mechanism is related to the inhibition of ER stress and downstream signaling pathways PERK/eIF2a, IRE1/JNK, and ATF6. In summary, we demonstrate that ox-LDL induced CMD by activating ER stress, propionate can effectively counteract the adverse effects of ox-LDL and protect coronary microcirculation function via inhibiting ER stress.