Impact of Cholesterol on Ischemic Stroke in Different Human-Like Hamster Models: A New Animal Model for Ischemic Stroke Study.

Lili Wei,George Liu,Xin Zhang,Xiao Lin,Xunde Xian,Yuhui Wang,Haozhe Shi

doi:10.3390/cells8091028

Abstract

Rationale: While high low-density lipoprotein cholesterol (LDL-C) and low high-density lipoprotein cholesterol (HDL-C) levels are positively associated with cardiovascular events, it is still unclear whether familial hypercholesterolemia (FH) and Tangier’s disease (TD), caused by mutations in LDLR and ABCA1, respectively, influence ischemic stroke (IS) in humans. Objective: We sought to establish an easier, more effective, and time-saving method to induce IS, then studied the precise effects of different types of lipoproteins on IS. Methods and Results: A new technique termed contralateral middle cerebral artery occlusion (c-MCAO) was introduced to human-like hamster models to induce IS. Compared to traditional distal MCAO (d-MCAO) induced by electrocoagulation, c-MCAO resulted in a more severe IS with larger infarct sizes and more blood–brain barrier (BBB) disruption after 24 h. It was shown that c-MCAO markedly elicited an increase in brain infarct volume and BBB leakage in both homozygous LDLR (LDLR–/–) and ABCA1 knockout (ABCA1–/–) hamsters, but not in heterozygous LDLR knockout (LDLR+/–) hamsters when compared to wild-type (WT) controls. Conclusions: Using human-like genetically engineered hamsters, our findings demonstrated that both high LDL-C level caused by homozygous LDLR deficiency and severe low HDL-C level caused by deleting ABCA1 were risk factors of IS. As such, we believe the development of this novel IS hamster model is suitable for future ischemic/reperfusion studies.

Highlights

Stroke is a leading cause of death and disability worldwide
Using human-like genetically engineered hamsters, our findings demonstrated that both high low density lipoprotein (LDL) cholesterol (LDL-C) level caused by homozygous LDL receptor (LDLR) deficiency and severe low high-density lipoprotein cholesterol (HDL-C) level caused by deleting ATP-binding cassette transporter member A1 (ABCA1) were risk factors of Ischemic stroke (IS)
Our results showed that the infiltration of CD68-positive macrophages into the ischemic brain was significantly increased in LDLR–/– and ABCA1–/– hamsters compared to WT and LDLR+/– hamsters

Summary

Introduction

Stroke is a leading cause of death and disability worldwide. Ischemic stroke (IS), accounting for approximately 80% of such cases [1,2], is characterized by the deprivation of blood supply following a thromboebolic occlusion of a major cerebral artery. Cholesterol is a major structural and functional component of cell membranes. It has been reported that elevated plasma cholesterol levels, especially in low density lipoprotein (LDL), are positively associated with the incidence of cardiovascular disease (CVD) [4,5,6,7]. LDL receptor (LDLR) is the most important protein for cholesterol transport. Loss-of-function mutations in LDLR, termed “familial hypercholesterolemia (FH)”, lead to a significantly increased serum LDL cholesterol (LDL-C) levels in patients, with cholesterol concentrations ranging from 350 to 500 mg/dL and 650 to

Objectives

Methods

Findings

Conclusion