Increased endoplasmic reticulum stress in atherosclerotic plaques associated with acute coronary syndrome.

Abstract

BACKGROUND:

The endoplasmic reticulum (ER) responds to various stresses by upregulation of ER chaperones, but 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:

Coronary artery segments were obtained at autopsy from 71 patients, and atherectomy specimens were obtained from 40 patients. Smooth muscle cells 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 of ER chaperone expression and apoptotic cells. ER chaperones also showed higher expression in atherectomy specimens from patients with unstable angina pectoris than in specimens from those with stable angina. Expression of 7-ketocholesterol was increased in the fibrous caps of thin-cap atheroma compared with thick-cap atheroma. Treatment of cultured coronary artery smooth muscle cells or THP-1 cells with 7-ketocholesterol induced upregulation of ER chaperones and apoptosis, whereas 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 small interfering RNA decreased ER stress-dependent death of cultured coronary artery smooth muscle cells and THP-1 cells.

CONCLUSIONS:

Increased ER stress occurs in unstable plaques. Our findings suggest that ER stress-induced apoptosis of smooth muscle cells and macrophages may contribute to plaque vulnerability.

• Authors: Masafumi Myoishi, Hiroyuki Hao, Tetsuo Minamino, Kouki Watanabe, Kensaku Nishihira, Kinta Hatakeyama, Yujiro Asada, Ken-ichiro Okada, Hatsue Ishibashi-Ueda, Giulio Gabbiani, Marie-Luce Bochaton-Piallat, Naoki Mochizuki, Masafumi Kitakaze
• Journal: Circulation (Circulation) Vol. 116 Issue 11 Pg. 1226-33 (Sep 11 2007) ISSN: 1524-4539 [Electronic] United States
• PMID: 17709641 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Molecular Chaperones

Topics

• Apoptosis (genetics)
• Cells, Cultured
• Coronary Artery Disease (genetics, metabolism)
• Coronary Vessels (metabolism)
• Endoplasmic Reticulum (genetics, metabolism)
• Humans
• Molecular Chaperones (biosynthesis, genetics)
• Myocardial Ischemia (genetics, metabolism)
• Up-Regulation (genetics)