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[Molecular and cellular mechanisms of arteriosclerosis and restenosis: possibilities of gene therapy]
T F Lüscher1, B S Oemar, Z Yang
1Kardiologie und Kardiovaskuläre Forschung, Universitätsklinik Inselspital, Bern, Schweiz.
Insights
Atherosclerosis, a leading cause of death, involves endothelial cells, platelets, and monocytes. Understanding cellular mechanisms and genetic factors is key to developing new therapies for this complex disease.
Area of Science:
- Cardiovascular Biology
- Molecular Medicine
- Pathogenesis of Atherosclerosis
Context:
- Atherosclerosis is a major cause of morbidity and mortality in Western countries, developing over decades with complex pathogenesis.
- The disease involves key cell types: endothelial cells, vascular smooth muscle cells, monocytes, and platelets.
- Cardiovascular risk factors like hyperlipidemia, hypertension, and diabetes accelerate endothelial dysfunction, promoting atherosclerotic processes.
Purpose:
- To explore the cellular and molecular mechanisms underlying atherosclerosis.
- To investigate the role of endothelial dysfunction in early atherogenesis.
- To identify differentially expressed genes in affected vessels for potential therapeutic targets.
Summary:
- Atherosclerosis pathogenesis involves endothelial cells, vascular smooth muscle cells, monocytes, and platelets, with endothelial dysfunction playing a critical early role.
- Cardiovascular risk factors exacerbate endothelial dysfunction, leading to lipid accumulation and vascular cell proliferation.
- Molecular biology techniques enable the identification of candidate genes for future genetic interventions, particularly for monogenetic diseases and potentially restenosis.
Impact:
- Expanded knowledge of cellular and molecular mechanisms in atherosclerosis.
- Highlights the early role of endothelial dysfunction in disease development.
- Suggests genetic interventions as a future therapeutic avenue, with potential applications in monogenetic diseases and restenosis.
Abstract:
Atherosclerosis and its consequences account for most of morbidity and mortality in Western countries. Atherosclerosis develops over a period of decades and has a complex pathogenesis. It is a disease of the intima and primarily involves four cell types, i.e., endothelial and vascular smooth muscle cells, monocytes and platelets. In recent years, knowledge on the cellular and molecular mechanisms of these cells and their alterations by cardiovascular risk factors and in atherosclerosis has greatly expanded. In particular, it became clear that endothelial cells play a crucial role in the regulation of platelet function, coagulation as well as vascular tone and structure. Interestingly, endothelial dysfunction occurs early, particularly if cardiovascular risk factors such as hyperlipidemia, hypertension and diabetes are present. This could lead to adhesion of circulating platelets and monocytes and increased accumulation of lipids in the subintima as well as increased contraction, migration and proliferation of vascular smooth muscle cells. The fact that atherosclerosis develops only in certain, but not in other parts of the circulation, however, has rarely been considered. With the development of molecular biology techniques it became possible to clone differentially expressed genes in vessels with or without atherosclerosis; this in turn allows to better characterize the molecular and cellular mechanisms of the disease. The search for such candidate genes could set the basis for future genetic interventions. This therapeutic approach is likely to reach clinical importance particularly in monogenetic diseases (i.e., familial hypercholesterinemia), while its use in complex polygenetic diseases such as atherosclerosis is more difficult. Restenosis, however, may be accessible to gene therapy earlier on as it is amenable to local gene transfection.