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

Area of Science:

• Neuroscience
• Cardiovascular Science
• Genetics

Background:

• High low-density lipoprotein cholesterol (LDL-C) and low high-density lipoprotein cholesterol (HDL-C) are linked to cardiovascular events.
• The specific impact of familial hypercholesterolemia (FH) and Tangier's disease (TD) on ischemic stroke (IS) risk in humans remains unclear.
• FH is caused by LDLR mutations, while TD results from ABCA1 mutations.

Purpose of the Study:

• To develop a more efficient method for inducing IS.
• To investigate the precise effects of different lipoprotein levels on IS.
• To assess the role of FH and TD in IS pathogenesis using a novel animal model.

Main Methods:

• A novel contralateral middle cerebral artery occlusion (c-MCAO) technique was employed in human-like hamster models to induce IS.
• The c-MCAO method was compared to traditional distal MCAO (d-MCAO).
• Homozygous and heterozygous LDLR knockout (LDLR-/- and LDLR+/-) and ABCA1 knockout (ABCA1-/-) hamsters were utilized, alongside wild-type (WT) controls.

Main Results:

• The c-MCAO technique induced more severe IS with larger infarct sizes and greater blood-brain barrier (BBB) disruption compared to d-MCAO.
• Both homozygous LDLR deficiency (high LDL-C) and ABCA1 deficiency (severe low HDL-C) significantly increased brain infarct volume and BBB leakage in hamsters.
• Heterozygous LDLR knockout hamsters did not show a significant increase in IS severity compared to WT controls.

Conclusions:

• High LDL-C levels (due to LDLR deficiency) and severely low HDL-C levels (due to ABCA1 deficiency) are identified as risk factors for IS.
• The developed c-MCAO hamster model is suitable for future studies on ischemic stroke and reperfusion.
• This study provides valuable insights into the genetic and lipid-related underpinnings of ischemic stroke.