Non-Mouse Models of Atherosclerosis: Approaches to Exploring the Translational Potential of New Therapies

Abstract

Cardiovascular disease is the largest single cause of disease-related mortality worldwide and the major underlying pathology is atherosclerosis. Atherosclerosis develops as a complex process of vascular lipid deposition and retention by modified proteoglycans, endothelial dysfunction and unresolved chronic inflammation. There are a multitude of current therapeutic agents, most based on lowering plasma lipid levels, but, overall, they have a lower than optimum level of efficacy and many deaths continue to arise from cardiovascular disease world-wide. To identify and evaluate potential novel cardiovascular drugs, suitable animal models that reproduce human atherosclerosis with a high degree of fidelity are required as essential pre-clinical research tools. Commonly used animal models of atherosclerosis include mice (ApoE−/−, LDLR−/− mice and others), rabbits (WHHL rabbits and others), rats, pigs, hamster, zebrafish and non-human primates. Models based on various wild-type and genetically modified mice have been extensively reviewed but mice may not always be appropriate. Thus, here, we provide an overview of the advantages and shortcomings of various non-mouse animal models of atherosclerotic plaque formation, and plaque rupture, as well as commonly used interventional strategies. Taken together, the combinatorial selection of suitable animal models readily facilitates reproducible and rigorous translational research in discovering and validating novel anti-atherosclerotic drugs.

A polyphenol-rich plant extract prevents hypercholesterolemia and modulates gut microbiota in western diet-fed mice

“…Secondly, in order to decipher the molecular mechanism of actions of Totum-070, genetically modified mouse models would be of great interest. For example, mice deficient for the cholesterol transporter NPC1L1 ( 120 ) or knock-out for the LDL-receptor ( 121 ) would help to understand the cholesterol-lowering effect of Totum-070 in the intestinal cholesterol absorption and through regulation of hepatic LDL-C clearance, respectively. Finally, future good quality clinical studies will have to confirm the hypocholesterolemic potential of this formulation in humans.…”

Totum-070, a Polyphenol-Rich Plant Extract, Prevents Hypercholesterolemia in High-Fat Diet-Fed Hamsters by Inhibiting Intestinal Cholesterol Absorption

“…Additionally, the actions of Totum-070 were limited to lipid homeostasis, and the potential effects of Totum-070 in preventing or delaying the atherosclerotic process were not covered in this study. Although hamsters exhibit metabolic similarities more comparable to humans than other rodents, they do not develop aortic atherosclerotic lesions [86]. Therefore, the use of a suitable preclinical model prone to atherosclerosis development, such as LDL receptor-or ApoE-deficient mice [86], will be required to evaluate the beneficial effects of Totum-070 on atherosclerosis.…”

“…Although hamsters exhibit metabolic similarities more comparable to humans than other rodents, they do not develop aortic atherosclerotic lesions [86]. Therefore, the use of a suitable preclinical model prone to atherosclerosis development, such as LDL receptor-or ApoE-deficient mice [86], will be required to evaluate the beneficial effects of Totum-070 on atherosclerosis. Finally, no adverse effects from Totum-070 supplementation were observed in our animal studies.…”

Inflammatory atherosclerotic plaque identification by SPECT/CT imaging of LFA-1 using [111In] In-DANBIRT in a novel dyslipidemic rat model

“…Rats have garnered increasing interest as an economical preclinical model that mimics key characteristics of atheroma; however, no model to date fully encapsulates the range of early vascular remodeling and T2D dysfunction observed clinically [9]. For instance, while the Zucker Diabetic Fatty (ZDF) rat is a well-studied model of T2D that reproduces features of human T2D, ZDF rats do not naturally develop atherosclerosis, but rather only demonstrate mild hyperlipidemia under a high-fat diet (HFD) [10,11].…”