Gene Therapy Targeting LDL Cholesterol but not HDL Cholesterol Induces Regression of Advanced Atherosclerosis in a Mouse Model of Familial Hypercholesterolemia

Li, Rongying; Chao, Hsu; Ko, Kerry W.S.; Cormier, S.; Dieker, Carrie; Nour, E. A.; Wang, Shining; Chan, Lawrence; Oka, Koichiro

doi:10.4172/2157-7412.1000106

Cited by 25 publications

(25 citation statements)

References 43 publications

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“…Furthermore, in Apoe −/− mice, infusion of recombinant ApoA1 lowers lipid and macrophage levels in the plaque [39]. However, adenoviral transfer of ApoA1 into Ldlr −/− mice has had inconsistent results [40]–[42]. In one study, preexisting atherosclerotic lesions regressed after ApoA1 gene transfer [41]; however, in other studies, regression was not detected, but progression was slowed, and plaques in the aortic root had fewer macrophages and more collagen content [40], [42].…”

Section: Discussionmentioning

confidence: 99%

“…However, adenoviral transfer of ApoA1 into Ldlr −/− mice has had inconsistent results [40]–[42]. In one study, preexisting atherosclerotic lesions regressed after ApoA1 gene transfer [41]; however, in other studies, regression was not detected, but progression was slowed, and plaques in the aortic root had fewer macrophages and more collagen content [40], [42]. Yet, the consensus is that increased levels HDL-cholesterol on top of LDL-cholesterol lowering could have additive effects on atherosclerosis regression and result in a more stable phenotype [39], [42], [43].…”

Section: Discussionmentioning

confidence: 99%

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Plasma Cholesterol–Induced Lesion Networks Activated before Regression of Early, Mature, and Advanced Atherosclerosis

et al. 2014

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Plasma cholesterol lowering (PCL) slows and sometimes prevents progression of atherosclerosis and may even lead to regression. Little is known about how molecular processes in the atherosclerotic arterial wall respond to PCL and modify responses to atherosclerosis regression. We studied atherosclerosis regression and global gene expression responses to PCL (≥80%) and to atherosclerosis regression itself in early, mature, and advanced lesions. In atherosclerotic aortic wall from Ldlr−/−Apob 100/100 Mttp flox/floxMx1-Cre mice, atherosclerosis regressed after PCL regardless of lesion stage. However, near-complete regression was observed only in mice with early lesions; mice with mature and advanced lesions were left with regression-resistant, relatively unstable plaque remnants. Atherosclerosis genes responding to PCL before regression, unlike those responding to the regression itself, were enriched in inherited risk for coronary artery disease and myocardial infarction, indicating causality. Inference of transcription factor (TF) regulatory networks of these PCL-responsive gene sets revealed largely different networks in early, mature, and advanced lesions. In early lesions, PPARG was identified as a specific master regulator of the PCL-responsive atherosclerosis TF-regulatory network, whereas in mature and advanced lesions, the specific master regulators were MLL5 and SRSF10/XRN2, respectively. In a THP-1 foam cell model of atherosclerosis regression, siRNA targeting of these master regulators activated the time-point-specific TF-regulatory networks and altered the accumulation of cholesterol esters. We conclude that PCL leads to complete atherosclerosis regression only in mice with early lesions. Identified master regulators and related PCL-responsive TF-regulatory networks will be interesting targets to enhance PCL-mediated regression of mature and advanced atherosclerotic lesions.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Plasma Cholesterol–Induced Lesion Networks Activated before Regression of Early, Mature, and Advanced Atherosclerosis

et al. 2014

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“…Li et al hypothesized that a possible explanation for there being no additive effects when coexpressing apo A-I along with lowering cholesterol could be due to the dysfunctional HDL that was produced by the apo A-I gene transfer. They concluded that it was possible that the artificially raised HDL was not functional in reverse cholesterol transport [17]. Furthermore, Van Craeyveld et al provide evidence to support Li et al's research where they noted that increased HDL cholesterol levels following apo A-I gene transfer did not induce regression of atherosclerosis [18].…”

Section: Transgenic Expression Of Hdl and Apo A-i In Mouse Modelsmentioning

confidence: 93%

The dual nature of HDL: Anti‐Inflammatory and pro‐Inflammatory

et al. 2015

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High density lipoprotein (HDL) has long been considered a protective factor against the development of coronary heart disease. Two important roles of HDL include reverse cholesterol transport (RCT) and the modulation of inflammation. The main protein component of HDL; apolipoprotein A-I (apo A-I) is primarily responsible for RCT. Apo A-I can be damaged by oxidative mechanisms, which reduce the protein's ability to promote RCT. In disease states such as diabetes, associated with a chronic acute-phase response, HDL has been found to be dysfunctional and pro-inflammatory. HDL cholesterol levels do not predict composition and/or function and therefore it is important to evaluate the quality and not just the quantity of HDL cholesterol when considering the risk of cardiovascular events. In clinical practice, there are currently no widely available tests for measuring the composition, functionality, and inflammatory properties of HDL. Small peptides that mimic some of the properties of apo A-I have been shown in pre-clinical models to improve HDL function and reduce atherosclerosis without altering HDL cholesterol levels. Clinical trials using HDL and HDL mimetics as therapeutic agents are currently underway. Results in animal studies and early clinical trials will be reviewed.

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“…The mice had been fed the atherogenic diet, however, for only 5 weeks before the viral treatments began, meaning that the regression induced by increasing the production of hAI was of early “fatty streak”-like plaques. Using a similar approach, Lawrence Chan and colleagues used an adenoviral vector expressing hAI in Ldlr−/− mice fed an atherogenic diet, but for a considerably longer period than the previous study (36 weeks) 29 . In contrast to the early lesions in Ldlr−/− mice, hAI expression was no longer sufficient to produce regression of lesion size.…”

Section: Hdl and Atherosclerosis Regression: Pre-clinical Modelsmentioning

confidence: 99%

High-Density Lipoprotein and Atherosclerosis Regression

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Hewing

Smith³

et al. 2014

Circulation Research

142

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High density lipoprotein particles (HDL) transport, among other molecules, cholesterol (HDL-C). In epidemiologic studies, plasma HDL-C levels have an inverse relationship to the risk of atherosclerotic cardiovascular disease (CVD). It has been assumed that this reflects the protective functions of HDL, which include their ability to promote cholesterol efflux. Yet, a number of recent pharmacological and genetic studies have failed to demonstrate that increased plasma levels of HDL-C resulted in decreased CVD risk, giving rise to a controversy over whether plasma levels of HDL-C reflect HDL function, or that HDL is even as protective as assumed. On balance, the evidence from pre-clinical and (limited) clinical studies show that HDL can promote the regression of atherosclerosis when the levels of functional particles are increased from endogenous or exogenous sources. The data show that regression results from a combination of reduced plaque lipid and macrophage contents, as well as from a reduction in its inflammatory state. While more research will be needed on basic mechanisms and to establish that these changes translate clinically to reduced CVD events, that HDL can regress plaques suggests that the recent trial failures do not eliminate HDL from consideration as an atheroprotective agent, but emphasizes the important distinction between HDL function and plasma levels of HDL-C.

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Gene Therapy Targeting LDL Cholesterol but not HDL Cholesterol Induces Regression of Advanced Atherosclerosis in a Mouse Model of Familial Hypercholesterolemia

Cited by 25 publications

References 43 publications

Plasma Cholesterol–Induced Lesion Networks Activated before Regression of Early, Mature, and Advanced Atherosclerosis

Plasma Cholesterol–Induced Lesion Networks Activated before Regression of Early, Mature, and Advanced Atherosclerosis

The dual nature of HDL: Anti‐Inflammatory and pro‐Inflammatory

High-Density Lipoprotein and Atherosclerosis Regression

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