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High density lipoproteins and coronary heart disease. Future prospects in gene therapy
1Départment d'Atherosclérose, INSERM U325, Institut Pasteur, Lille, France.
Insights
Low high-density lipoprotein (HDL) cholesterol is linked to heart disease. Gene therapy targeting apolipoprotein A-I (apo A-I) and lecithin-cholesterol acyltransferase (LCAT) may increase HDL levels and combat atherosclerosis.
Area of Science:
- Cardiovascular Science
- Gene Therapy
- Metabolic Disorders
Background:
- Atherosclerosis cardiovascular disease is a leading global cause of mortality.
- Hypercholesterolemia and dyslipoproteinemia are primary risk factors for coronary heart disease.
- Low serum high-density lipoprotein (HDL) cholesterol is a prevalent abnormality in patients with coronary artery disease.
Purpose of the Study:
- To investigate the potential of increasing serum HDL cholesterol concentration to improve reverse cholesterol transport.
- To evaluate the therapeutic efficacy of targeting apolipoprotein A-I (apo A-I) and lecithin-cholesterol acyltransferase (LCAT) for atherosclerosis treatment.
Main Methods:
- Studies utilizing transgenic mice and rabbits overexpressing human apo A-I or human lecithin-cholesterol acyl-transferase (LCAT).
- Adenovirus-mediated gene transfer of human apo A-I and LCAT in mice.
Main Results:
- Overexpression of apo A-I and LCAT in transgenic models increased serum HDL cholesterol concentration.
- Overexpression of apo A-I and LCAT reduced diet-induced atherogenesis in animal models.
- Adenovirus-mediated gene transfer successfully increased circulating apo A-I and LCAT levels in mice.
Conclusions:
- Apo A-I and LCAT are promising therapeutic targets for gene therapy in atherosclerosis.
- Increasing HDL cholesterol through gene therapy may offer a novel strategy for managing atherosclerosis associated with low HDL levels.
Abstract:
Atherosclerosis cardiovascular disease is the leading cause of death in industrial societies. For coronary heart disease, hypercholesterolemia and dyslipoproteinemia are the major risk factors. Low serum levels of cholesterol in the HDL fraction is the most common abnormality found in patients with confirmed coronary artery disease. A therapeutical strategy consists in increasing the serum HDL cholesterol concentration in order to improve the 'reverse cholesterol transport'. Studies in transgenic mice and rabbits for human apo A-I or human lecithin cholesterol acyl-transferase showed that overexpression of these proteins increases serum HDL cholesterol concentration and reduces diet induced atherogenesis. Furthermore, adenovirus-mediated transfer of human apo A-I and LCAT genes in mice also increases circulating apo A-I and LCAT. Apo A-I and LCAT are two potential targets for gene therapy of patients with atherosclerosis associated with a low HDL cholesterol level.