Melatonin attenuates high-fat diet- and particulate matter-induced cardiac injury: involvement of mitochondrial quality and miR-221/222 expression

Abstract

Previous studies have shown that exposure to hyperlipidemia or particulate matter (PM) individually affects the progression of cardiovascular disease (CVD), but the combined effects of these factors remain understudied. This study investigated whether combined treatment with a high-fat diet (HFD)/palmitate (PA) and PM exacerbates cardiomyocyte injury and proposed using the antioxidant melatonin. Furthermore, we explored the role of mitochondria and miR-221/222 in melatonin-mediated reduction of HFD- and PM-exacerbated cardiomyocyte injury. H9c2 cells were treated with or without 50 μM PA, 10 μg/mL PM, and 100 μM melatonin for 24 h. In the in vivo experiments, 8–12-week-old wild-type (WT) mice, miR-221/222 knockout (miR-221/222^–/-) mice, and miR-221/222 overexpression (miR-221/222^o/e) mice were treated with HFD for 4 weeks. PM was injected intratracheally at the end of the second and third weeks, and melatonin 20 mg/kg was administered orally daily starting at the end of the second week. Combined PA/HFD and PM induced mitochondrial ROS accumulation, subsequent mitochondrial fission, and excessive mitophagy in cardiomyocytes and cardiac tissues. This cascade increases cardiomyocyte apoptosis and fibrosis, leading to cardiac dysfunction. Melatonin treatment reduced mitochondrial ROS accumulation and improved HFD- and PM-induced cardiac dysfunction. Further exploration of the molecular mechanism highlighted that miR-221/222 upregulation is a downstream effect of melatonin, revealing a novel regulatory pathway for HFD- and PM-induced cardiac injury. This study showed that simultaneous exposure to HFD/PA and PM exacerbated cardiomyocyte apoptosis and fibrosis. These effects could be ameliorated by melatonin-mediated ROS scavenging, maintenance of mitochondrial function, and cardioprotection associated with miR-221/222.