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Published on: July 27, 2018
Lipid lowering and HDL raising gene transfer increase endothelial progenitor cells, enhance myocardial vascularity,
Stephanie C Gordts1, Eline Van Craeyveld, Ilayaraja Muthuramu
1Center for Molecular and Vascular Biology, Catholic University of Leuven, Leuven, Belgium.
Insights
Gene transfer to lower cholesterol or raise HDL improved endothelial progenitor cell function, myocardial vascularity, and cardiac diastolic function in mice. These findings suggest potential therapeutic benefits for cardiovascular health.
Area of Science:
- Cardiovascular Biology
- Gene Therapy
- Lipid Metabolism
Background:
- Hypercholesterolemia and low HDL cholesterol are risk factors for coronary heart disease and heart failure.
- The direct impact of lipid levels on myocardial function requires further investigation.
- Endothelial progenitor cells (EPCs) play a crucial role in vascular health and repair.
Purpose of the Study:
- To investigate if lipid-lowering or HDL-raising gene transfer enhances EPC number and function.
- To determine if these interventions improve myocardial vascularity and cardiac function in mice.
- To test the hypothesis that improved EPCs lead to better cardiac outcomes.
Main Methods:
- Adenoviral vectors were used for gene transfer to lower LDL cholesterol (AdLDLr) or raise HDL (AdA-I) in LDL receptor-deficient mice.
- EPC number and function (migration, adhesion) were assessed.
- Myocardial capillary density and relative vascularity were quantified.
- Cardiac diastolic function was evaluated using echocardiography.
Main Results:
- AdLDLr transfer increased circulating EPCs by 2-fold and improved EPC function.
- AdLDLr treatment led to a 28% increase in myocardial capillary density and 22% higher relative vascularity.
- AdLDLr and AdA-I gene transfer significantly improved diastolic function parameters.
- HDL-raising gene transfer also enhanced EPC number and function, and myocardial vascularity.
Conclusions:
- Both lipid-lowering and HDL-raising gene transfer demonstrate beneficial effects on EPC biology.
- These interventions positively impact myocardial vascularity and diastolic cardiac function.
- Findings challenge the external validity of studies on myocardial biology in normocholesterolemic animal models.
Background:
Hypercholesterolemia and low high density lipoprotein (HDL) cholesterol contribute to coronary heart disease but little is known about their direct effects on myocardial function. Low HDL and raised non-HDL cholesterol levels carried increased risk for heart failure development in the Framingham study, independent of any association with myocardial infarction. The objective of this study was to test the hypothesis that increased endothelial progenitor cell (EPC) number and function after lipid lowering or HDL raising gene transfer in C57BL/6 low density lipoprotein receptor deficient (LDLr(-/-)) mice may be associated with an enhanced relative vascularity in the myocardium and an improved cardiac function.
Methodology/Principal Findings:
Lipid lowering and HDL raising gene transfer were performed using the E1E3E4-deleted LDLr expressing adenoviral vector AdLDLr and the human apolipoprotein A-I expressing vector AdA-I, respectively. AdLDLr transfer in C57BL/6 LDLr(-/-) mice resulted in a 2.0-fold (p<0.05) increase of the circulating number of EPCs and in an improvement of EPC function as assessed by ex vivo EPC migration and EPC adhesion. Capillary density and relative vascularity in the myocardium were 28% (p<0.01) and 22% (p<0.05) higher, respectively, in AdLDLr mice compared to control mice. The peak rate of isovolumetric relaxation was increased by 12% (p<0.05) and the time constant of isovolumetric relaxation was decreased by 14% (p<0.05) after AdLDLr transfer. Similarly, HDL raising gene transfer increased EPC number and function and raised both capillary density and relative vascularity in the myocardium by 24% (p<0.05). The peak rate of isovolumetric relaxation was increased by 16% (p<0.05) in AdA-I mice compared to control mice.
Conclusions/Significance:
Both lipid lowering and HDL raising gene transfer have beneficial effects on EPC biology, relative myocardial vascularity, and diastolic function. These findings raise concerns over the external validity of studies evaluating myocardial biology and cardiac repair in normocholesterolemic animals.
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