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Atherosclerotic plaque rupture: emerging insights and opportunities
1Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA.
Abstract:
Reduction in acute,coronary events requires interventions that affect the mechanisms leading to formation of atherosclerotic lesions, as well as the molecular events that precipitate acute myocardial infarction. Data from clinical trials indicate that it is the vulnerability of atherosclerotic plaque to rupture, rather than the degree of atherosclerosis, that is the primary determinant of thrombosis-mediated acute coronary events. The characteristics of a plaque that is vulnerable to rupture include a thin fibrous cap separating the circulation from procoagulants in the plaque's lipid core; increased numbers of inflammatory cells (e.g., macrophages and T cells); and a relative paucity of vascular smooth muscle cells (VSMC). Plaque stability reflects various dynamic factors: interaction of inflammatory cells, VSMC production of the extracellular matrix that is the bulwark of the fibrous cap, inhibition of this process by certain cytokines, and increased degradation of the matrix by matrix metalloproteinases. There is growing interest in the concept that intervention in the inflammatory processes of atherogenesis might reduce lesion formation and/or progression. There has also been substantial progress in understanding the transcriptional regulation of proteins that are critically involved in atherogenesis. Recently, peroxisomal proliferator-activated receptors (PPARs) have been identified as a potential link between insulin resistance and atherosclerosis. This concept is supported by the discovery through drug screening of thiazolidinediones (troglitazone, rosiglitazone), compounds that are not only ligands for PPARgamma, a nuclear receptor involved in adipogenesis, but also are antidiabetic agents.
Insights
Preventing acute coronary events involves targeting vulnerable atherosclerotic plaques. Interventions may focus on inflammation and transcriptional regulation, with peroxisome proliferator-activated receptors (PPARs) showing promise.
Area of Science:
- Cardiovascular Medicine
- Molecular Biology
- Pharmacology
Background:
- Acute coronary events are primarily driven by vulnerable atherosclerotic plaque rupture, not just plaque volume.
- Plaque vulnerability is characterized by a thin fibrous cap, inflammatory cells, and reduced vascular smooth muscle cells (VSMC).
- Plaque stability is influenced by inflammatory cell interactions, VSMC extracellular matrix production, and matrix metalloproteinase activity.
Purpose of the Study:
- To explore interventions targeting mechanisms of atherosclerotic lesion formation and plaque rupture.
- To investigate the role of inflammation and transcriptional regulation in atherogenesis.
- To examine the link between insulin resistance, atherosclerosis, and peroxisome proliferator-activated receptors (PPARs).
Main Methods:
- Analysis of clinical trial data on acute coronary events and plaque characteristics.
- Review of factors influencing plaque stability, including cellular interactions and matrix degradation.
- Examination of recent findings on transcriptional regulation and the identification of PPARs.
Main Results:
- Clinical data suggest plaque vulnerability, not degree of atherosclerosis, dictates thrombosis-mediated events.
- Key features of vulnerable plaques include thin fibrous caps, increased inflammatory cells, and decreased VSMC.
- Peroxisome proliferator-activated receptors (PPARs) are identified as a potential link between insulin resistance and atherosclerosis.
- Thiazolidinediones, ligands for PPARgamma, demonstrate both antidiabetic and potential anti-atherosclerotic properties.
Conclusions:
- Interventions targeting inflammatory processes in atherogenesis may reduce lesion formation and progression.
- Understanding transcriptional regulation, particularly involving PPARs, is crucial for developing new therapeutic strategies.
- PPARs and related compounds like thiazolidinediones offer a potential therapeutic avenue for managing both insulin resistance and atherosclerosis.