Low-density lipoprotein receptor gene transfer in hypercholesterolemic mice improves cardiac function after myocardial infarction

Craeyveld, Eline Van; Jacobs, Frank; Gordts, Stephanie C.; Geest, Bart De

doi:10.1038/gt.2011.147

Cited by 35 publications

(40 citation statements)

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“…Van Craeyveld et al [76] As stated supra, high non-HDL cholesterol levels were independently associated with heart failure incidence after adjustment for interim myocardial infarction and clinical covariates in Framingham Heart Study participants free of coronary heart disease at baseline [69]. These prospective data are in agreement with earlier cross-sectional 415 studies showing that post-infarct ejection fraction is lower in patients with elevated non-HDL cholesterol levels [77,78].…”

Section: Non-hdl Lipoproteinssupporting

confidence: 82%

Role of lipids and lipoproteins in myocardial biology and in the development of heart failure

Muthuramu¹,

Singh²,

Amin³

et al. 2015

Clinical Lipidology

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As the population ages, heart failure will continue to be a growing public health 30 problem. Metabolic homeostasis in the heart requires a fine-tuning of metabolism of different substrates. Notwithstanding a retro control of fatty acid and glucose utilization, the heart functions best when it oxidizes both substrates simultaneously.Mismatch between the uptake and oxidation of long-chain fatty acids in the myocardium induces lipotoxicity characterized by the accumulation of triglycerides, 35 diacylglycerols, ceramides, and other lipids. Lipotoxicity may result in cardiomyocyte apoptosis, interstitial fibrosis, and cardiac dysfunction, and may promote insulin resistance. In this review, we will highlight the impact of lipids and lipoproteins on myocardial biology and on the development of heart failure independent of their effects on coronary heart disease. 40 45 KEY WORDSHeart failure, cardiac metabolism, fatty acids, lipotoxicity, hypercholesterolemia, high-density lipoproteins 50 3

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Section: Non-hdl Lipoproteinssupporting

confidence: 82%

Role of lipids and lipoproteins in myocardial biology and in the development of heart failure

Muthuramu¹,

Singh²,

Amin³

et al. 2015

Clinical Lipidology

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“…Control mice were injected with the same dose of Adnull (n = 7) or with saline buffer (n = 6). The equivalency of Adnull and saline controls with regard to different outcome measures has been demonstrated in several studies [14], [18], [19], which indicates that the E1E3E4-deleted adenoviral vectors per se do not affect results in one or another direction. Therefore and since no difference or trend for difference was observed between the Adnull and saline injected mice for all parameters investigated in the current study, data of both control groups were consistently pooled.…”

Section: Methodsmentioning

confidence: 79%

“…Furthermore, in patients with a first myocardial infarction, hypercholesterolemia is associated with a more pronounced deterioration of the left ventricular function [13]. In agreement, hypercholesterolemia in C57BL/6 low density lipoprotein receptor ( Ldlr ) −/− mice results in more pronounced adverse ventricular remodelling and in a worse cardiac function after permanent ligation of the left anterior descending coronary artery (LAD) [14].…”

Section: Introductionmentioning

confidence: 79%

Selective Homocysteine Lowering Gene Transfer Improves Infarct Healing, Attenuates Remodelling, and Enhances Diastolic Function after Myocardial Infarction in Mice

et al. 2013

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Background and aimsHomocysteine levels predict heart failure incidence in prospective epidemiological studies and correlate with severity of heart failure in cross-sectional surveys. The objective of this study was to evaluate whether a selective homocysteine lowering intervention beneficially affects cardiac remodelling and cardiac function after myocardial infarction (MI) in a murine model of combined hypercholesterolemia and hyperhomocysteinemia.Methodology and principal findingsA selective homocysteine lowering gene transfer strategy was evaluated in female C57BL/6 low density lipoprotein receptor (Ldlr)−/− cystathionine-ß-synthase (Cbs)+/− deficient mice fed a hyperhomocysteinemic and high saturated fat/high cholesterol diet using an E1E3E4-deleted hepatocyte-specific adenoviral vector expressing Cbs (AdCBS). MI was induced by permanent ligation of the left anterior descending coronary artery 14 days after saline injection or gene transfer. AdCBS gene transfer resulted in a persistent more than 5-fold (p<0.01) decrease of plasma homocysteine levels and significantly improved endothelial progenitor cell function. Selective homocysteine lowering enhanced infarct healing as indicated by a 21% (p<0.01) reduction of infarct length at day 28 after MI and by an increased number of capillaries and increased collagen content in the infarct zone. Adverse remodelling was attenuated in AdCBS MI mice as evidenced by a 29% (p<0.05) reduction of left ventricular cavity area at day 28, by an increased capillary density in the remote myocardium, and by reduced interstitial collagen. The peak rate of isovolumetric relaxation was increased by 19% (p<0.05) and the time constant of left ventricular relaxation was reduced by 21% (p<0.05) in AdCBS MI mice compared to control MI mice, indicating improved diastolic function.Conclusion/significanceSelective homocysteine lowering gene transfer improves infarct healing, attenuates remodelling, and significantly enhances diastolic function post-MI in female C57BL/6 Ldlr −/− Cbs +/− mice. The current study corroborates the view that hyperhomocysteinemia exerts direct effects on the myocardium and may potentiate the development of heart failure.

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“…In pathological hypertrophy, mismatch between cardiomyocyte size and vascularity may induce myocardial hypoxia and cardiomyocyte death, which may accelerate progression to congestive heart failure [27]. Therefore, hypercholesterolemia is expected to speed up heart failure development under conditions of increased load, which was indeed observed in a model of post-myocardial infarction remodeling [21]. Furthermore, oxygen extraction of the myocardium at rest is approximately 75%.…”

Section: Discussionmentioning

confidence: 96%

Lipid Lowering and HDL Raising Gene Transfer Increase Endothelial Progenitor Cells, Enhance Myocardial Vascularity, and Improve Diastolic Function

et al. 2012

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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.

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Low-density lipoprotein receptor gene transfer in hypercholesterolemic mice improves cardiac function after myocardial infarction

Cited by 35 publications

References 50 publications

Role of lipids and lipoproteins in myocardial biology and in the development of heart failure

Role of lipids and lipoproteins in myocardial biology and in the development of heart failure

Selective Homocysteine Lowering Gene Transfer Improves Infarct Healing, Attenuates Remodelling, and Enhances Diastolic Function after Myocardial Infarction in Mice

Lipid Lowering and HDL Raising Gene Transfer Increase Endothelial Progenitor Cells, Enhance Myocardial Vascularity, and Improve Diastolic Function

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