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Quantification of Atherosclerosis in Mice
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Quantification of Atherosclerosis in Mice

Published on: June 12, 2019

Long-term Expression of Apolipoprotein B mRNA-specific Hammerhead Ribozyme via scAAV8.2 Vector Inhibits

Hersharan Nischal1, Hua Sun, Yuchun Wang

  • 1Center for Human Genetics, Brown Foundation Institute of Molecular Medicine, the University of Texas Health Science Center, Houston, Texas, USA.

Molecular Therapy. Nucleic Acids
|October 3, 2013
PubMed

Insights

Hammerhead ribozymes targeting apolipoprotein B (apoB) mRNA significantly reduced atherosclerosis in mice. This gene silencing therapy lowered apoB and triglyceride levels, offering a potential treatment for cardiovascular disease.

Area of Science:

  • Molecular Biology
  • Gene Therapy
  • Cardiovascular Research

Background:

  • Apolipoprotein B (apoB) overproduction is linked to coronary artery disease.
  • Hammerhead ribozymes can inhibit gene expression by cleaving specific mRNA.
  • Atherosclerosis development is a complex process involving lipid metabolism.

Purpose of the Study:

  • To investigate the long-term effect of reducing apoB gene expression on atherosclerosis development using hammerhead ribozymes.
  • To assess the efficacy of specific ribozymes (RB1, RB15) delivered via scAAV8.2 vector in a mouse model.
  • To determine the impact of apoB reduction on lipid profiles and atherosclerotic lesions.

Main Methods:

  • Design and delivery of two target substrate-specific hammerhead ribozymes (RB1, RB15) against apoB mRNA using scAAV8.2 vectors.
  • Treatment of atherosclerosis-prone LDb mice (Ldlr(-/-)Apobec1(-/-)) with active ribozymes, a combination, or an inactive mutant.
  • Measurement of plasma apoB, triglyceride levels, Dgat1 mRNA, and diacylglycerol (DAG) species, alongside analysis of atherosclerotic lesions.

Main Results:

  • Significant reduction in plasma triglyceride and apoB levels in mice treated with RB1, RB15, or the RB1/RB15 combination.
  • Marked decrease in the extent of atherosclerotic lesions in treated mice compared to controls.
  • Downregulation of diacylglycerol acyltransferase 1 (Dgat1) mRNA and diacylglycerol (DAG) molecular species following active ribozyme treatment.

Conclusions:

  • Hammerhead ribozyme-mediated reduction of apoB gene expression effectively inhibits atherosclerosis development in LDb mice.
  • Decreased apoB levels correlate with reduced Dgat1 expression and triglyceride levels, impacting atherosclerosis.
  • This study provides evidence for ribozyme-based gene silencing as a therapeutic strategy for atherosclerosis.

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