INCREASED ENDOPLASMIC RETICULUM STRESS AND NRF2 REPRESSION IN PERIPHERAL BLOOD MONONUCLEAR CELLS OF PATIENTS WITH STABLE CORONARY ARTERY DISEASE

Endoplasmic reticulum (ER) stress is involved in the pathophysiology of atherosclerosis. Insults interfering with endoplasmic reticulum (ER) function, lead to accumulation of unfolded and misfolded proteins in ER that initiates the unfolded protein response (UPR). When the UPR fails to control the level of unfolded and misfolded proteins, ER-initiated apoptotic signaling is induced. We evaluated: 1) the UPR and ER-initiated apoptotic signaling in peripheral blood mononuclear cells (PBMC) of stable coronary artery disease patients (CAD); 2) PBMC content of oxidation products of phospholipid 1-palmitoyl-2-arachidonyl-sn-glycero-3-phosphorylcholine (oxPAPC); 3) the possible origin of oxPAPC in PBMC; 4) the expression of nuclear erytroid-related factor 2 (Nrf2)/antioxidant related element (ARE), a cellular defence mechanism. 29 CAD and 28 matched controls were enrolled. Expression of glucose-regulated protein 78 kDa (GRP78/BiP) as representative of UPR, and of C/EBP homologous protein (CHOP) as representative of ER-apoptosis, were significantly higher in CAD than in controls (p<0.01). Concentrations of oxPAPC in PBMC, in plasma and in low density lipoprotein (LDL) resulted significantly higher in CAD than in controls (p<0.01). The oxPAPC in PBMC may derive from circulating ox-LDL. Nrf2/ARE gene expression and circulating and cellular glutathione (GSH) were significantly lower in CAD than in controls (p<0.01). In in vitro studies, increasing amounts of oxPAPC induced a dose-dependent increase of CHOP and apoptosis-related protein expression (p<0.01) and a progressive decrease of Nrf2/ARE gene expression (p<0.01). In PBMC of CAD patients there is an activation of UPR and of ER-initiated apoptotic signaling, possibly related to abnormal concentration of oxPAPC in PBMC.