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Pluripotential mechanisms of cardioprotection with HMG-CoA reductase inhibitor therapy.
Am J Cardiovasc Drugs. 2001; 1(6):411-20.AJ

Abstract

Treatment with hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitors has been accompanied by a reduced risk of cardiovascular events. Rapid onset of clinical benefit and weak correlations between plasma low density lipoprotein-cholesterol levels and coronary lumen change or cardiovascular events indicates that nonlipid mechanisms are involved in this beneficial effects with HMG-CoA reductase inhibitors. Furthermore, more rapid onset of clinical benefit with HMG-CoA reductase inhibitors in patients with acute coronary syndromes or acute myocardial infarction than in those with stable coronary heart disease suggest that HMG-CoA reductase inhibitors facilitate repair of ruptured or ulcerated atherosclerotic plaque, facilitate plaque stabilization and/or reduce thrombus formation on ruptured plaques. Treatment with HMG-CoA reductase inhibitors improved endothelial dysfunction in patients with hypercholesterolemia and this improvement in endothelial function was not correlated with reduction in total serum cholesterol levels. Similarly, reduction in endothelial pre-proendothelin mRNA expression and endothelin synthesis and blood pressure lowering with HMG-CoA reductase inhibitors occurred independent of lipid-lowering. Finally, HMG-CoA reductase inhibitors increased endothelial nitric oxide levels i.e. upregulated endothelial nitric oxide synthetase expression via post-transcriptional mechanisms and prevented its down-regulation by oxidized LDL-C. HMG-CoA reductase inhibitors have been shown to modulate the immune response by inhibiting activation of immune-competent cells such as macrophages, and antigen presentation to macrophages by T cells. Treatment with HMG-CoA reductase inhibitors can reduce expression, production and circulating levels of chemokines (monocyte chemoattractant protein-1) and proinflammatory cytokines [tumor necrosis factoralpha, interleukin (IL)-6 and IL-1beta]. HMG-CoA reductase inhibitors reduced inflammation in human atheroma: significantly fewer macrophages and T cells, less oxidized LDL-C and higher collagen content. In addition, treatment with HMG-CoA reductase inhibitor led to decreased cell death within the atheroma. Treatment with these agents also reduced expression of inducible cellular adhesion molecules, decreased secretion of metalloproteinases by macrophages, reduced vascular smooth muscle cell apoptosis. Lastly, HMG-CoA reductase inhibitors appear to have important effects on the thrombogenesis: reduced expression of tissue factor production and activity; increased production of tissue factor package inhibitor; decreased platelet thrombus formation and improved fibrinolysis as a result of lowered plasminogen activator inhibitor-1 levels. As the pluripotential cardioprotective mechanisms of HMG-CoA reductase inhibitors are further elucidated, it is envisaged that treatment with HMG-CoA reductase inhibitors will be initiated earlier and more frequently in patients with hypercholesterolemia.

Authors+Show Affiliations

Preventive Cardiology Center, Division of Cardiology, Department of Medicine and Preventive Medicine, Northwestern University Medical School, Chicago, Illinois 60611, USA. r-rosenson@northwestern.edu

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't
Review

Language

eng

PubMed ID

14728000

Citation

Rosenson, R S.. "Pluripotential Mechanisms of Cardioprotection With HMG-CoA Reductase Inhibitor Therapy." American Journal of Cardiovascular Drugs : Drugs, Devices, and Other Interventions, vol. 1, no. 6, 2001, pp. 411-20.
Rosenson RS. Pluripotential mechanisms of cardioprotection with HMG-CoA reductase inhibitor therapy. Am J Cardiovasc Drugs. 2001;1(6):411-20.
Rosenson, R. S. (2001). Pluripotential mechanisms of cardioprotection with HMG-CoA reductase inhibitor therapy. American Journal of Cardiovascular Drugs : Drugs, Devices, and Other Interventions, 1(6), 411-20.
Rosenson RS. Pluripotential Mechanisms of Cardioprotection With HMG-CoA Reductase Inhibitor Therapy. Am J Cardiovasc Drugs. 2001;1(6):411-20. PubMed PMID: 14728000.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Pluripotential mechanisms of cardioprotection with HMG-CoA reductase inhibitor therapy. A1 - Rosenson,R S, PY - 2004/1/20/pubmed PY - 2004/4/9/medline PY - 2004/1/20/entrez SP - 411 EP - 20 JF - American journal of cardiovascular drugs : drugs, devices, and other interventions JO - Am J Cardiovasc Drugs VL - 1 IS - 6 N2 - Treatment with hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitors has been accompanied by a reduced risk of cardiovascular events. Rapid onset of clinical benefit and weak correlations between plasma low density lipoprotein-cholesterol levels and coronary lumen change or cardiovascular events indicates that nonlipid mechanisms are involved in this beneficial effects with HMG-CoA reductase inhibitors. Furthermore, more rapid onset of clinical benefit with HMG-CoA reductase inhibitors in patients with acute coronary syndromes or acute myocardial infarction than in those with stable coronary heart disease suggest that HMG-CoA reductase inhibitors facilitate repair of ruptured or ulcerated atherosclerotic plaque, facilitate plaque stabilization and/or reduce thrombus formation on ruptured plaques. Treatment with HMG-CoA reductase inhibitors improved endothelial dysfunction in patients with hypercholesterolemia and this improvement in endothelial function was not correlated with reduction in total serum cholesterol levels. Similarly, reduction in endothelial pre-proendothelin mRNA expression and endothelin synthesis and blood pressure lowering with HMG-CoA reductase inhibitors occurred independent of lipid-lowering. Finally, HMG-CoA reductase inhibitors increased endothelial nitric oxide levels i.e. upregulated endothelial nitric oxide synthetase expression via post-transcriptional mechanisms and prevented its down-regulation by oxidized LDL-C. HMG-CoA reductase inhibitors have been shown to modulate the immune response by inhibiting activation of immune-competent cells such as macrophages, and antigen presentation to macrophages by T cells. Treatment with HMG-CoA reductase inhibitors can reduce expression, production and circulating levels of chemokines (monocyte chemoattractant protein-1) and proinflammatory cytokines [tumor necrosis factoralpha, interleukin (IL)-6 and IL-1beta]. HMG-CoA reductase inhibitors reduced inflammation in human atheroma: significantly fewer macrophages and T cells, less oxidized LDL-C and higher collagen content. In addition, treatment with HMG-CoA reductase inhibitor led to decreased cell death within the atheroma. Treatment with these agents also reduced expression of inducible cellular adhesion molecules, decreased secretion of metalloproteinases by macrophages, reduced vascular smooth muscle cell apoptosis. Lastly, HMG-CoA reductase inhibitors appear to have important effects on the thrombogenesis: reduced expression of tissue factor production and activity; increased production of tissue factor package inhibitor; decreased platelet thrombus formation and improved fibrinolysis as a result of lowered plasminogen activator inhibitor-1 levels. As the pluripotential cardioprotective mechanisms of HMG-CoA reductase inhibitors are further elucidated, it is envisaged that treatment with HMG-CoA reductase inhibitors will be initiated earlier and more frequently in patients with hypercholesterolemia. SN - 1175-3277 UR - https://www.unboundmedicine.com/medline/citation/14728000/Pluripotential_mechanisms_of_cardioprotection_with_HMG_CoA_reductase_inhibitor_therapy_ L2 - https://dx.doi.org/10.2165/00129784-200101060-00001 DB - PRIME DP - Unbound Medicine ER -