The short-chain fatty acid propionate prevents ox-LDL-induced coronary microvascular dysfunction by alleviating endoplasmic reticulum stress in HCMECs

• Published in: PloS one 2024-05, Vol.19 (5), p.e0304551
• Main Authors: Hong, Dan, Tang, Wen, Li, Fei, Liu, Yating, Fu, Xiao, Xu, Qin
• Format: Article
• Language: English
• Subjects: Activating Transcription Factor 6 - metabolism; Angina pectoris; Arterioles; Atherosclerosis; Biology and Life Sciences; Cardiology; Cardiomyopathy; Cardiovascular disease; Cardiovascular diseases; Coronary Vessels - drug effects; Coronary Vessels - metabolism; Development and progression; eIF-2 Kinase - metabolism; Endoplasmic reticulum; Endoplasmic Reticulum Chaperone BiP; Endoplasmic Reticulum Stress - drug effects; Endothelial cells; Endothelial Cells - drug effects; Endothelial Cells - metabolism; Endothelium; Endothelium-derived relaxing factors; Fatty acids; Fatty Acids, Volatile - metabolism; Fatty Acids, Volatile - pharmacology; Fermentation; Heat-Shock Proteins - metabolism; Humans; Initiation factor eIF-2; Intestinal microflora; Lipids; Lipoproteins, LDL - metabolism; Low density lipoprotein; Low density lipoproteins; Medicine and Health Sciences; Metabolic disorders; Microbiomes; Microcirculation - drug effects; Microvasculature; Nitric oxide; Nitric Oxide - metabolism; Nitric Oxide Synthase Type III - metabolism; Nitric-oxide synthase; Pathogenesis; Phosphorylation; Phosphorylation - drug effects; Physical Sciences; Prevention; Propionates - pharmacology; Propionic acid; Protein expression; Proteins; Research and Analysis Methods; Signal transduction; Signal Transduction - drug effects; Umbilical vein; Vasodilation
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0304551

Coronary microvascular dysfunction (CMD) is a critical pathogenesis of 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. However, the relationship between ox-LDL and coronary microcirculation has yet to be assessed. Short-chain fatty acid (SCFA), a fermentation product of the gut microbiome, could improve endothelial-dependent vasodilation in human adipose arterioles, but the effect of SCFA on coronary microcirculation is unclear. In this study, we found ox-LDL stimulated expression of ER chaperone GRP78. Further, we activated downstream PERK/eIF2a, IRE1/JNK, and ATF6 signaling pathways, decreasing eNOS phosphorylation and NO production in human cardiac microvascular endothelial. Furthermore, SCFA-propionate can inhibit ox-LDL-induced eNOS phosphorylation reduction and 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.