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Permanent Ligation of the Left Anterior Descending Coronary Artery in Mice: A Model of Post-myocardial Infarction Remodelling and Heart Failure

Heart failure is a syndrome in which the heart fails to pump blood at a rate commensurate with cellular oxygen requirements at rest or during stress. It ...

Catholic University of Leuven

Hyperhomocysteinemia is an independent risk factor for ischemic cardiovascular diseases, but its causal role in atherothrombosis remains controversial. Proatherogenic and/or prothrombotic effects may underlie the potential causal relation between hyperhomocysteinemia and cardiovascular events. Here, the effects of selective lowering of plasma homocysteine, plasma cholesterol, or both on endothelial function and on atherogenesis in male hyperlipidemic and hyperhomocysteinemic C57BL/6 low-density lipoprotein receptor (LDLr)(-/-)/cystathionine-β-synthase (CBS)(+/-)-deficient mice were investigated. Second, we evaluated whether selective homocysteine lowering has anti-thrombotic effects in a model of arterial thrombosis. A hyperhomocysteinemic and atherogenic diet was started at the age of 12 weeks. Three weeks later, gene transfer was performed with E1E3E4-deleted adenoviral vectors for hepatocyte-restricted overexpression of CBS (AdCBS) or of the LDLr (AdLDLr), or with the control vector Adnull. In a fourth group, AdCBS and AdLDLr were co-administered. Selective homocysteine lowering but not selective cholesterol lowering restored endothelial function at 6 weeks after gene transfer. Intimal area in the aortic root and in the brachiocephalic artery at 13 weeks was more than 100-fold (p < 0.001) smaller in AdLDLr and AdCBS/AdLDLr mice than in control mice and AdCBS mice. No differences in intimal area were observed between control mice and AdCBS mice. In a model of carotid artery thrombosis, the average time to first occlusion and to stable occlusion were 1.9-fold (p < 0.01) and 2.1-fold longer (p < 0.01), respectively, in AdCBS-treated mice than in control mice. Taken together, these data show that correction of endothelial dysfunction following selective homocysteine lowering has anti-thrombotic but no anti-atherogenic effects.

Correction of endothelial dysfunction after selective homocysteine lowering gene therapy reduces arterial thrombogenicity but has no effect on atherogenesis.

Insulin promotes adhesion of leukocytes to the endothelium through increased expression of surface adhesion molecules. We determined whether src-homology domain-2-containing protein tyrosine phosphatase 2 (SHP2), a downstream effecter of insulin signaling, is involved in insulin-induced endothelial inflammation.

Protein tyrosine phosphatase SHP2 mediates chronic insulin-induced endothelial inflammation.

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.

Lipid lowering and HDL raising gene transfer increase endothelial progenitor cells, enhance myocardial vascularity, and improve diastolic function.

Homocysteine 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.

Selective homocysteine lowering gene transfer improves infarct healing, attenuates remodelling, and enhances diastolic function after myocardial infarction in mice.

The liver is a target for gene therapy of inborn errors of metabolism, of hemophilia, and of acquired diseases such as liver cancer and hepatitis. The ideal gene transfer strategy should deliver the transgene DNA to parenchymal liver cells with accuracy and precision in the absence of side effects. Liver sinusoids are highly specialized capillaries with a particular endothelial lining: the endothelium contains open fenestrae, whereas a basal lamina is lacking. Fenestrae provide a direct access of gene transfer vectors to the space of Disse, in which numerous microvilli from parenchymal liver cells protrude. The small diameter of fenestrae in humans constitutes an anatomical barrier for most gene transfer vectors with the exception of adeno-associated viral (AAV) vectors. Recent studies have demonstrated the superiority of novel AAV serotypes for hepatocyte-directed gene transfer applications based on enhanced transduction, reduced prevalence of neutralizing antibodies, and diminished capsid immune responses. In a landmark clinical trial, hemophilia B was successfully treated with an AAV8 human factor IX expressing vector. Notwithstanding significant progress, clinical experience with these technologies remains very limited and many unanswered questions warrant further study. Therefore, the field should continue to progress as it has over the past decade, cautiously and diligently.

The liver as a target organ for gene therapy: state of the art, challenges, and future perspectives.

Chronic non-healing wounds lead to considerable morbidity and mortality. Pleiotropic effects of high density lipoproteins (HDL) may beneficially affect wound healing. The objectives of this murine study were: (1) to investigate the hypothesis that hypercholesterolemia induces impaired wound healing and (2) to study the effect of topical HDL administration in a model of delayed wound healing. A circular full thickness wound was created on the back of each mouse. A silicone splint was used to counteract wound contraction. Coverage of the wound by granulation tissue and by epithelium was quantified every 2 days. Re-epithelialization from day 0 till day 10 was unexpectedly increased by 21.3% (p < 0.05) in C57BL/6 low density lipoprotein (LDLr) deficient mice with severe hypercholesterolemia (489 ± 14 mg/dL) compared to C57BL/6 mice and this effect was entirely abrogated following cholesterol lowering adenoviral LDLr gene transfer. In contrast, re-epithelialization in hypercholesterolemic (434 ± 16 mg/dL) C57BL/6 apolipoprotein (apo) E-/- mice was 22.6% (p < 0.0001) lower than in C57BL/6 mice. Topical HDL gel administered every 2 days increased re-epithelialization by 25.7% (p < 0.01) in apo E-/- mice. In conclusion, topical HDL application is an innovative therapeutic strategy that corrects impaired wound healing in apo E-/- mice.

Ilayaraja Muthuramu

Department of Cardiovascular Sciences,
Centre for Molecular and Vascular Biology,
Department of Cardiovascular Sciences, Centre for Molecular and Vascular Biology

Catholic University of Leuven

Permanent Ligation of the Left Anterior Descending Coronary Artery in Mice: A Model of Post-myocardial Infarction Remodelling and Heart Failure

Ilayaraja Muthuramu

.css-o250i3{font-size:18px;font-family:Open Sans,sans-serif;line-height:21.6px;}Department of Cardiovascular Sciences,Centre for Molecular and Vascular Biology,Department of Cardiovascular Sciences, Centre for Molecular and Vascular Biology

Catholic University of Leuven

Permanent Ligation of the Left Anterior Descending Coronary Artery in Mice: A Model of Post-myocardial Infarction Remodelling and Heart Failure

Department of Cardiovascular Sciences,
Centre for Molecular and Vascular Biology,
Department of Cardiovascular Sciences, Centre for Molecular and Vascular Biology