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Probucol prevents early coronary heart disease and death in the high-density lipoprotein receptor SR-BI/apolipoprotein E double knockout mouse.

Publication ,  Journal Article
Braun, A; Zhang, S; Miettinen, HE; Ebrahim, S; Holm, TM; Vasile, E; Post, MJ; Yoerger, DM; Picard, MH; Krieger, JL; Andrews, NC; Simons, M; Krieger, M
Published in: Proc Natl Acad Sci U S A
June 10, 2003

Mice with homozygous null mutations in the high-density lipoprotein receptor SR-BI (scavenger receptor class B, type I) and apolipoprotein E genes fed a low-fat diet exhibit a constellation of pathologies shared with human atherosclerotic coronary heart disease (CHD): hypercholesterolemia, occlusive coronary atherosclerosis, myocardial infarctions, cardiac dysfunction (heart enlargement, reduced systolic function and ejection fraction, and ECG abnormalities), and premature death (mean age 6 weeks). They also exhibit a block in RBC maturation and abnormally high plasma unesterified-to-total cholesterol ratio (0.8) with associated abnormal lipoprotein morphology (lamellar/vesicular and stacked discoidal particles reminiscent of those in lecithin/cholesterol acyltransferase deficiency and cholestasis). Treatment with the lipid-lowering, antiatherosclerosis, and antioxidation drug probucol extended life to as long as 60 weeks (mean 36 weeks), and at 5-6 weeks of age, virtually completely reversed the cardiac and most RBC pathologies and corrected the unesterified to total cholesterol ratio (0.3) and associated distinctive abnormal lipoprotein morphologies. Manipulation of the timing of administration and withdrawal of probucol could control the onset of death and suggested that critical pathological changes usually occurred in untreated double knockout mice between approximately 3 (weaning) and 5 weeks of age and that probucol delayed heart failure even after development of substantial CHD. The ability of probucol treatment to modulate pathophysiology in the double knockout mice enhances the potential of this murine system for analysis of the pathophysiology of CHD and preclinical testing of new approaches for the prevention and treatment of cardiovascular disease.

Duke Scholars

Published In

Proc Natl Acad Sci U S A

DOI

ISSN

0027-8424

Publication Date

June 10, 2003

Volume

100

Issue

12

Start / End Page

7283 / 7288

Location

United States

Related Subject Headings

  • Scavenger Receptors, Class B
  • Receptors, Scavenger
  • Receptors, Lipoprotein
  • Receptors, Immunologic
  • Probucol
  • Myocardium
  • Mice, Knockout
  • Mice, Inbred C57BL
  • Mice
  • Membrane Proteins
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Braun, A., Zhang, S., Miettinen, H. E., Ebrahim, S., Holm, T. M., Vasile, E., … Krieger, M. (2003). Probucol prevents early coronary heart disease and death in the high-density lipoprotein receptor SR-BI/apolipoprotein E double knockout mouse. Proc Natl Acad Sci U S A, 100(12), 7283–7288. https://doi.org/10.1073/pnas.1237725100
Braun, Anne, Songwen Zhang, Helena E. Miettinen, Shamsah Ebrahim, Teresa M. Holm, Eliza Vasile, Mark J. Post, et al. “Probucol prevents early coronary heart disease and death in the high-density lipoprotein receptor SR-BI/apolipoprotein E double knockout mouse.Proc Natl Acad Sci U S A 100, no. 12 (June 10, 2003): 7283–88. https://doi.org/10.1073/pnas.1237725100.
Braun A, Zhang S, Miettinen HE, Ebrahim S, Holm TM, Vasile E, et al. Probucol prevents early coronary heart disease and death in the high-density lipoprotein receptor SR-BI/apolipoprotein E double knockout mouse. Proc Natl Acad Sci U S A. 2003 Jun 10;100(12):7283–8.
Braun, Anne, et al. “Probucol prevents early coronary heart disease and death in the high-density lipoprotein receptor SR-BI/apolipoprotein E double knockout mouse.Proc Natl Acad Sci U S A, vol. 100, no. 12, June 2003, pp. 7283–88. Pubmed, doi:10.1073/pnas.1237725100.
Braun A, Zhang S, Miettinen HE, Ebrahim S, Holm TM, Vasile E, Post MJ, Yoerger DM, Picard MH, Krieger JL, Andrews NC, Simons M, Krieger M. Probucol prevents early coronary heart disease and death in the high-density lipoprotein receptor SR-BI/apolipoprotein E double knockout mouse. Proc Natl Acad Sci U S A. 2003 Jun 10;100(12):7283–7288.
Journal cover image

Published In

Proc Natl Acad Sci U S A

DOI

ISSN

0027-8424

Publication Date

June 10, 2003

Volume

100

Issue

12

Start / End Page

7283 / 7288

Location

United States

Related Subject Headings

  • Scavenger Receptors, Class B
  • Receptors, Scavenger
  • Receptors, Lipoprotein
  • Receptors, Immunologic
  • Probucol
  • Myocardium
  • Mice, Knockout
  • Mice, Inbred C57BL
  • Mice
  • Membrane Proteins