P5402Inhibition of microRNA-210 as a novel therapeutic strategy to protect against atherosclerosis development

Abstract

Abstract Background MicroRNAs are involved in many processes such as cell proliferation and differentiation, angiogenesis, apoptosis, mitochondrial metabolism and DNA damage repair. Circulating levels of microRNA-210 (miR-210) are associated with the risk for cardiovascular mortality at patients with coronary artery disease. Purpose The aim was to investigate the effects and involved mechanisms of a novel treatment, miR-210 inhibitor (antagomiR-210), on the activation of inflammation and immune system, and overproduction of reactive oxygen species in atherosclerosis. Methods Golden Syrian hamsters were divided into: (1) simultaneously hypertensive - hyperlipidemic (HH) by combining two feeding conditions for 4 months, that mimic atherosclerosis; (2) HH with subcutaneous injection at months 1,2,3 containing antagomiR-210, or scramble (Scr)-miR negative control, or vehicle (phosphate-buffered saline, PBS) alone; (3) controls (C), age-matched normal healthy animals. Results The results showed that atherosclerosis significantly increased miR-210 levels in circulation, liver and thoracic aorta, which were abolished by antagomiR-210 administration. The preventive treatment of atherosclerosis with antagomiR-210 induced the following effects: (i) reduced the cholesterol, triglyceride and hepatic enzyme levels in plasma; (ii) increased the levels of circulating endothelial progenitor cells and reduced circulating microvesicle concentrations; (iii) improved endothelial cell functions; (iv) lowered inflammation by the reduction of TNF-α levels in plasma and infiltrated macrophage number into liver and thoracic aorta; (v) diminished immune system activation by decreasing the PD-1 levels in circulation, PD-L1/PD-L2 expression in liver/thoracic aorta and T cell number infiltrated into liver/thoracic aorta; (vii) reduced oxidative stress by decreasing O2·− generation into liver/thoracic aorta; (viii) lowered the expression of miR-210 target protein, protein tyrosine phosphatase 1B (PTP1B), in plasma/liver/thoracic aorta, and of its downstream molecules (PI3K, AKT1/2/3, eNOS, ERK1/2) in liver and thoracic aorta. Conclusion The results revealed the antagomiR-210 ability to modulate the pro-inflammatory, immune-stimulatory and pro-oxidant microenvironment within the atherosclerotic animal model, via direct targeting to PTP-1B and PI3K/AKT/eNOS and MAPK/ERK/ROS as downstream pathways. In summary, our data provide new insight in molecular basis of an encouraging therapeutic strategy based on miR-210 inhibition for the treatment of atherosclerosis and cardiovascular disease. Acknowledgement/Funding CNCS-UEFISCDI, projects no. PN-III-P1-1.2-PCCDI-2017-0527 and no. PN-III-P1-1.2-PCCDI-2017-0797, and by the Romanian Academy