Coronary Microembolization Induces Cardiomyocyte Apoptosis Through the LOX-1-Dependent Endoplasmic Reticulum Stress Pathway Involving JNK/P38 MAPK.

Lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) is a membrane protein associated with apoptosis. Endoplasmic reticulum (ER) stress-induced apoptosis has been determined in several cardiovascular diseases. Mitogen-activated protein kinase (MAPK) signalling is involved in apoptosis. The aim of this study was to investigate whether LOX-1, ER stress, and MAPKs play a role in cardiomyocyte apoptosis after coronary microembolization (CME) and the exact mechanisms involved. Thirty swine were randomized into the following groups (n = 5 per group): sham, CME, CME + LOX-1 small-interfering RNA (siRNA), CME + control siRNA, CME + JNK inhibitor, and CME + p38 inhibitor. The CME model was established by injecting microspheres into the left anterior descending (LAD) artery, whereas swine in the sham group received normal saline instead. Twelve hours after the sham operation or CME, cardiac function, serum c-troponin I level, microinfarcts, and apoptotic index were determined. Relative expression levels of LOX-1, ER stress markers (glucose-regulated protein 78 [GRP 78], C/EBP homologous protein [CHOP], and cleaved caspase-12), cleaved caspase-3, c-Jun NH2-terminal protein kinases (JNK), p38, and extracellular signal-related protein kinases (ERK1/2) were measured. CME induced cardiac dysfunction, microinfarction, increased serum c-troponin I levels, and cardiomyocyte apoptosis. Additionally, the expression of LOX-1, ER stress markers, and cleaved caspase-3, and the phosphorylation of JNK, p38, and ERK1/2 were all enhanced. LOX-1 siRNA inhibited these effects except the phosphorylation of ERK1/2. Pretreatment with a JNK inhibitor or a p38 inhibitor attenuated the expression of ER stress markers and apoptosis. Our results indicated that CME induced cardiomyocyte apoptosis through the LOX-1-dependent ER stress pathway, in which the phosphorylation of JNK and p38 were involved. This might provide a new approach for the prevention and treatment of CME.