334 - Mitochondrial Stress in Monocytes Is Reflected in Microvesicles and Associated with Metabolic and Coronary Artery Diseases

Abstract

Background Cytochrome oxidase (COX) IV complex regulates energy production in mitochondria. Impaired COX gene expression is related to obesity and type 2 diabetes, but whether it is directly related to the incidence of cardiovascular events is unknown. We investigated whether COX gene expression in monocytes is predictive for cardiovascular events in CAD patients. We then aimed to validate our findings in monocyte-derived microvesicles isolated from plasma. Finally, we determined their association with atherosclerosis in mice and pigs. Methods and results We enrolled 142 consecutive patients undergoing diagnostic coronary angiography between June 2010 and January 2011, and followed 67 patients with stable CAD prospectively for at least 3 years. Twenty-two patients experienced a new cardiovascular event (32.8%). Circulating CD14+ monocytes and microvesicles were isolated with magnetic beads and mRNA levels were measured with qPCR. Patients in lowest tertile of mitochondrial cyochrome oxidase 1 (MT-COI ) in monocytes at baseline had a higher risk for developing a new event after adjusting for age, gender, (ex)smoking, BMI, blood pressure, diabetes, LDL- and HDL-cholesterol, triglycerides, hs-CRP, IL-6, and number of diseased vessels (HR: 3.95; 95% CI: 1.63 – 9.57). Patients in lowest tertile of MT-CO1 in monocyte-specific microvesicles had also a higher risk of developing a new event (adjusted HR: 5.00; 95% CI: 1.77 – 14). In the aortic arch of obese mice and the LAD of overweight pigs, low aortic Mt-co1 was associated with M1 phenotype of macrophages and higher oxidized LDL associated with larger plaque size. Conclusions In the current blinded study, low MT-COI in monocytes identifies an at-risk population for new cardiovascular events in CAD patients. For the first time, we show that signatures in monocyte-specific microvesicles in plasma have similar predictive properties. We confirmed association of low MT-COI with atherosclerosis in two preclinical models.