Effects Of Proinflammatory High Density Lipoprotein On Nrf2 Signalling And Foam Cell Formation In Macrophage Of Coronary Artery Disease Patients

Background: High density lipoprotein (HDL) from coronary artery disease (CAD) patients display proinflammatory properties, which persuades LDL oxidation and foam cell formation in monocytes/macrophages (Mo/MΦ). Nrf2/antioxidant signalling are crucial for maintaining the redox milieu, but these mechanisms are remain elusive in the setting of pro-inflammatory HDL ( pi HDL) mediated atherosclerosis and coronary artery disease (CAD). Methods: In healthy humans (n=20) and CAD patients (n=20), we assessed Nrf2 signalling, paraoxonase-1 activity, HDL function and foam cell formation in the circulating Mo/MΦ. Results: We observed a range of HDL activity (20-80%) in healthy humans, indicating that the HDL function varies among normal individuals. In comparison with functional HDL ( f HDL), pi HDL demonstrated decreased paraoxonase-1 activity (41.38±6.71 vs. 118.04±11.18; p<0.05), higher levels of lipid peroxides (0.95±0.09 vs. 0.02±0.01; p<0.05), higher triglyceride (75.4±6.79 vs. 31.76±4.19; p<0.05) and phospholipid levels (74.09±5.9 vs. 46.47±6.11; p<0.05) in CAD patients vs . healthy humans. Interestingly, we noticed an increase in MMP9 along with enhanced pi HDL in CAD patients, a previously unrecognized event, which might accelerate atherosclerosis in these individuals. Despite an increased Nrf2 nuclear translocation, we noticed significant decrease in the levels of antioxidant enzymes in the macrophages treated with pi HDL. It is likely that pi HDL mediated Nrf2 activation could be a compensatory response to ROS/oxidative stress in CAD patients, but insufficient antioxidant system might have resulted in enhanced foam cell formation. Conclusions: Taken together, these results suggest that pi HDL could be a key regulator of Nrf2 signalling in the Mo/MΦ of CAD patients. Thus, an early screening and identification of dysfunctional HDL (i.e. pi HDL) is crucial for vascular health, thereby preventing the progression of CAD.