Understanding hyperlipidemia and atherosclerosis: lessons from genetically modified apoe and ldlr mice

Abstract

Hyperlipidemia is the most important risk factor for atherosclerosis, which is the major cause of cardiovascular disease. The etiology of hyperlipidemia and atherosclerosis is complex and governed by multiple interacting genes. However, mutations in two genes have been shown to be directly involved, i.e., the low-density lipoprotein receptor (LDLR) and apolipoprotein E (ApoE). Genetically modified mouse models have been instrumental in elucidating the underlying molecular mechanisms in lipid metabolism. In this review, we focus on the use of two of the most widely used mouse models, ApoE- and LDLR-deficient mice. After almost a decade of applications, it is clear that each model has unique strengths and drawbacks when carrying out studies of the role of additional genes and environmental factors such as nutrition and lipid-lowering drugs. Importantly, we elaborate on mice expressing mutant forms of APOE, including the APOE3Leiden ( APOE3L ) and the APOE2 knock-in ( APOE 2k) mouse models. These models have outstanding potential, as they are highly responsive to dietary factors and pharmacological interventions.

Transplantation of Mesenchymal Cells Rejuvenated by the Overexpression of Telomerase and Myocardin Promotes Revascularization and Tissue Repair in a Murine Model of Hindlimb Ischemia

“…Similarly, when ApoE −/− mice (8-12 months old) are fed a normal chow diet, they develop spontaneous atherosclerosis that results in the narrowing of the vessel lumen, which leads to the progressive restriction of blood flow at multiple arterial branches, including the hindlimb vessels. [40][41][42] Thus, for our study, we used 12-monthold ApoE −/− mice as cell therapy recipients because they develop chronic atherosclerosis similar to the atherosclerotic lesions observed in humans. In agreement with previous reports, we found that baseline blood flow in the nonischemic limb was better in C57 mice than in ApoE −/− mice.…”

Hawthorn Fruit Attenuates Atherosclerosis by Improving the Hypolipidemic and Antioxidant Activities in Apolipoprotein E-Deficient Mice

“…In the present study, we used the apoE −/− mouse model since its pathogenesis of atherosclerosis resembles that observed in humans and it has been widely applied in cardiovascular research 22,23) . We investigated the mechanisms of hawthorn fruit in apoE −/− mice from the two aspects of hypolipidemic and antioxidant activities.…”

Allograft Vasculopathy Versus Atherosclerosis

“…Many investigators use this knockout when studying other genes involved in atherosclerosis that are not involved in lipid metabolism. 66 The major drawback to the apoE-KO model, however, is the difference in lipoprotein profiles as compared with most humans. In addition, drugs such as statins and fibrates may have disparate effects on these mice as compared with humans.…”

“…In addition, drugs such as statins and fibrates may have disparate effects on these mice as compared with humans. 66 The LDLR-KO mouse model compensates for the cholesterol composition; however, it does not develop complex "humanized" plaques without alteration to the diet. 66 The LDLR-KO model has shown promise in bone marrow transplantation studies, a strategy not as effective in apoE-KO because apoE from transplanted bone marrow can rescue the KO characteristics.…”