Stabilization of atherosclerotic plaque during lipid lowering.
Lipid lowering therapy leads to a great reduction of cardiovascular complications, but has almost no effect on the degree of stenosis of coronary arteries. These findings have lead to a new paradigm of coronary artery disease, i.e. clinical prognosis is not only determined by the extent of a single stenosis, but mainly by the number and structure of atherosclerotic plaque. Rupture of an instable or vulnerable plaque, characterized by a large lipid-rich central core, inflammatory cells, and a thin fibrous cap, causes sudden thrombus formation and thereby acute coronary syndromes. There is accumulating evidence that cholesterol lowering can result in plaque stabilization and improvement of endothelial dysfunction, reviewed recently in this journal. Accordingly, this review focuses on new molecular mechanisms which provide evidence that reduction of cellular cholesterol activates novel transcription factors, called sterol regulatory element binding proteins, which can regulate not only the LDL receptor, thereby reducing plasma cholesterol levels, but also a diverse number of other genes. These gene regulatory events might link cholesterol lowering not only to cellular cholesterol metabolism, but also to triglyceride metabolism, cell differentiation and other events potentially stabilizing vulnerable plaque.
Müller-Wieland
D
D
Clinic II and Poliklinik for Internal Medicine, University of Cologne, Germany.
Kotzka
J
J
Krone
W
W
D000924:Anticholesteremic Agents / Q000627:therapeutic use*; D001161:Arteriosclerosis / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D022762:CCAAT-Enhancer-Binding Proteins; D004268:DNA-Binding Proteins / Q000502:physiology; D004730:Endothelium, Vascular / Q000473:pathology / Q000503:physiopathology; D005786:Gene Expression Regulation; D006801:Humans; D009687:Nuclear Proteins / Q000502:physiology; D011973:Receptors, LDL / Q000235:genetics; D051780:Sterol Regulatory Element Binding Protein 1; D051782:Sterol Regulatory Element Binding Protein 2; D014157:Transcription Factors / Q000502:physiology
D000924:Anticholesteremic Agents; D022762:CCAAT-Enhancer-Binding Proteins; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; D011973:Receptors, LDL; C497387:SREBF1 protein, human; C497390:SREBF2 protein, human; D051780:Sterol Regulatory Element Binding Protein 1; D051782:Sterol Regulatory Element Binding Protein 2; D014157:Transcription Factors