Recombinant apolipoprotein A-I Milano rapidly reverses aortic valve stenosis and decreases leaflet inflammation in an experimental rabbit model.

Abstract

AIMS:

Aortic stenosis (AS) is associated with significant morbidity and mortality. Recombinant apolipoprotein A-I Milano (rApoA-I(M)) induces atherosclerotic plaque regression. The aims of this study were to determine the effects of rApoA-I(M) on experimental aortic valve degeneration and its mechanisms of action.

METHODS AND RESULTS:

New Zealand White rabbits (n = 20) were fed an atherogenic diet for 9 months and then randomized to either placebo or rApoA-I(M). Echocardiography was used to assess the effect of the treatments on AS. Porcine aortic valve myofibroblasts (PAVMF) treated with oxidized low-density lipoprotein served to define the effects of rApoA-I(M) on the expression of monocyte chemoattractant protein-1 (MCP-1), nuclear factor (NF)-kappaB, and alkaline phosphatase (AP). Recombinant apolipoprotein A-I Milano increased aortic valve area (AVA) by 32% (0.25 +/- 0.05 to 0.34 +/- 0.07 cm(2), P < 0.01); whereas AVA remained unchanged in the placebo group (0.24 +/- 0.05 to 0.26 +/- 0.04 cm(2), P = 0.58). Histopathological examination of aortic valves in the rApoA-I(M) animals showed significantly less leaflet thickening, inflammation, and calcification vs. the placebo group. In vitro, rApoA-I(M) significantly inhibited MCP-1, AP, and NF-kappaB and decreased intracellular cholesterol content in PAVMF.

CONCLUSION:

Recombinant apolipoprotein A-I Milano treatment reverses AS in this experimental rabbit model. The beneficial effects seem to be mediated by enhanced cholesterol removal and by reduced inflammation and calcification.

• Authors: Walter S Speidl, Giovanni Cimmino, Borja Ibanez, Sammy Elmariah, Randolph Hutter, Mario J Garcia, Valentin Fuster, Martin E Goldman, Juan J Badimon
• Journal: European heart journal (Eur Heart J) Vol. 31 Issue 16 Pg. 2049-57 (Aug 2010) ISSN: 1522-9645 [Electronic] England
• PMID: 20304838 (Publication Type: Journal Article)

Chemical References

• Anti-Inflammatory Agents
• Apolipoprotein A-I
• Recombinant Proteins
• apolipoprotein A-I Milano
• Alkaline Phosphatase

Topics

• Alkaline Phosphatase (drug effects)
• Animals
• Anti-Inflammatory Agents (therapeutic use)
• Aortic Valve Stenosis (drug therapy, pathology)
• Apolipoprotein A-I (therapeutic use)
• Calcinosis (pathology)
• Myofibroblasts (pathology)
• Plaque, Atherosclerotic (pathology)
• Rabbits
• Random Allocation
• Recombinant Proteins (therapeutic use)