Abstract
BackgroundHypercholesterolemia 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 findingsLipid 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/SignificanceBoth 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.
Highlights
Hypercholesterolemia and low high density lipoprotein (HDL) cholesterol contribute to coronary heart disease but little is known about their direct effects on myocardial function
We evaluated the effect of lipid lowering gene transfer and HDL raising gene transfer on endothelial progenitor cell (EPC) number and EPC function, on relative myocardial vascularity, and on cardiac function in C57BL/6 low density lipoprotein receptor deficient (LDLr2/2) mice
The main findings of the current study are that 1) both lipid lowering and HDL raising gene transfer markedly increase EPC number and enhance EPC function in C57BL/6 LDLr2/2 mice; 2) capillary density and relative vascularity in the myocardium are increased by lowering of non-HDL lipoproteins and raising of HDL lipoproteins; and 3) diastolic cardiac function is significantly improved following lipid lowering and HDL augmenting gene transfer
Summary
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 heart failure risk during follow-up in the Framingham study independent of any association with myocardial infarction [4]. Data on the effect of cholesterol on in vivo systolic and diastolic function are paralleled by observations in isolated cardiomyocytes showing a decrease in the maximum rate of cardiomyocyte shortening and the maximum rate of cardiomyocyte relaxation [7,8] Based on these observations, the term ‘cholesterol cardiomyopathy’ has been introduced [7]. 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 (LDLr2/ 2) mice may be associated with an enhanced relative vascularity in the myocardium and an improved cardiac function
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