Abstract 590: Increased Endoplasmic Reticulum Stress in Atherosclerotic Plaques Associated With Acute Coronary Syndrome
Background Endoplasmic reticulum (ER) responds to various stresses by up-regulation of ER chaperones, and prolonged ER stress eventually causes apoptosis. Although apoptosis is considered to be essential for the progression and rupture of atherosclerotic plaques, the influence of ER stress and apoptosis on rupture of unstable coronary plaques remains unclear.
Methods and Results We obtained 152 coronary artery segments at autopsy and 40 atherectomy specimens from 71 and 40 patients, respectively . Smooth muscle cells (SMCs) and macrophages in the fibrous caps of thin cap atheroma and ruptured plaques, but not in the fibrous caps of thick cap atheroma and fibrous plaques, showed a marked increase in the expression of ER chaperone and numbers of apoptotic cells. ER chaperones also expressed higher in atherectomy specimens from patients with unstable angina pectoris than with stable angina. To explore the plausible molecular mechanism of activation of ER stress and the mechanistic link to apoptosis, we investigated plaque lipids such as oxysterols. Among oxysterols, expression of 7-ketocholesterol was increased in the fibrous caps of thin cap atheroma compared with thick cap atheroma. Treatment of either cultured coronary artery SMCs or THP-1 cells with 7-ketocholesterol induced upregulation of ER chaperones and apoptosis, while these changes were prevented by antioxidants. We also investigated possible signaling pathways for ER-initiated apoptosis and found that the CHOP (a transcription factor induced by ER stress)-dependent pathway was activated in unstable plaques. In addition, knockdown of CHOP expression by siRNA decreased ER stress-dependent death of cultured coronary artery SMCs and THP-1 cells.
Conclusions Increased ER stress occurs in unstable plaques. Our findings suggest that ER stress-induced apoptosis of SMCs and macrophages may contribute to plaque vulnerability.