Omega-3 PUFAs Reduce Inflammation by Targeting NRF2 and NF-κB activity in an Ex-Vivo Model of Cardiac mature Adipocytes and adipose derived stem cells from Atherosclerotic Patients

Abstract

Under proatherogenic conditions, epicardial (EAT) and pericardial adipose tissue (PAT) acquire inflammatory/pro-atherogenic phenotypes that contribute to coronary atherosclerosis. Recent data have highlighted a significant inverse relationship between levels of n-3 polyunsaturated fatty acids(PUFAs) eicosapentaenoic acid(EPA) and docosahexaenoic acid (DHA) in adipose tissue and risk of myocardial infarction. Our study aimed at investigating whether DHA/EPA supplementation of cardiac fat adipocytes attenuates cardiac adipose tissue inflammation. To this aim mature adipocytes and adipose stem cell were isolated from PAT samples collected from coronary artery disease (CAD) patients undergoing coronary artery bypass grafting, exposed to DHA/EPA ex-vivo, and evaluated for pro-inflammatory gene expression and activity. PAT adipocytes and stem cells exposure to DHA led to a significant increase in the membrane ratio of omega-3 to omega-6 PUFAs and decreased mRNA expression levels of monocyte chemoattractant protein(MCP)-1, interleukin(IL)-6, matrix metalloproteinase(MMP)-9 and CXC motif chemokine ligand(CXCL)10 (p < 0.05). This downregulation was accompanied by increased expression of uncoupling proteins(UCP)1 and 2 and heme-oxygenase(HO)-1 and of the anti-inflammatory and pro-resolving lipid mediator resolvin D1. Mechanistically, this protective modulation appears to be driven by the upregulation of peroxisome proliferator-activated receptor gamma(PPAR)-γ and nuclear factor erythroid 2-related factor(NRF)2, leading to increased NRF2 activity and suppressed NF-κB signaling. Functionally, supernatants from DHA-conditioned adipocytes exhibited reduced monocyte-attracting activity in chemotaxis assays. While EPA conditioning produced effects similar to DHA, arachidonic acid(AA) showed no significant biological effects. In conclusion, DHA and EPA mitigated PAT inflammatory profile, highlighting the potential therapeutic role of such PUFAs in reducing cardiac adipose tissue inflammation. These results may have implications for treatment of CAD patients.