Abstract 13572: The Mammalian Target of Rapamycin Activation is Required for Monocyte Proinflammatory Response in Patients with Coronary Artery Disease

Introduction and Hypothesis: The regulation of nuclear factor kappa B (NF-kappaB) signaling and systematic proinflammatory response in atherosclerosis (AS) remain poorly defined. Therefore, we investigated the relationship between mammalian target of rapamycin (mTOR) and NF-kappaB signaling under proinflammatory state of circulating mononuclear cell (MNC) in coronary artery disease (CAD) patients. Methods: MNC was isolated from fasting blood samples of CAD patients (n = 31) and control subjects (n = 35). Serum interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α) were measured by enzyme-linked immunosorbent assay. NF-kappaB activity, p-mTOR and mTOR expression, and p65 nuclear translocation were analyzed by western blot in the isolated MNC. In vitro, Serum extracted from CAD patients (CAD serum) was used to treat MNC isolated from the control subjects. Pharmacological and genetic inhibitors of mTOR were also applied. Results: The serum IL-6 and TNF-α concentrations, NF-kappaB activity and p65 nuclear translocation in MNC were significantly elevated in the CAD group, and mTOR phosphorylation in MNC was also higher compared with control group. Serum extracted from CAD patients (CAD serum) induced a time-dependent phosphorylation of mTOR in parallel with aberrant NF-kappaB activation and the upregulation of inflammatory factors. Inhibition of mTOR with pharmacological or genetic means abolished CAD serum-triggered NF-kappaB activation and proinflammatory response. Moreover, lipid lowering drug statins partly, but not completely, blocked CAD serum-activated mTOR and proinflammatory responses. Conclusion: Our data demonstrate that the mTOR activation is required for the proinflammatory response via NF-kappaB-dependent pathway in MNC, which suggests underlying mechanism of atherosclerosis and more importantly, potential strategies to attenuate atherosclerosis in clinical practice.