Recombinant apolipoprotein A-I Milano shows anti-atherosclerotic promise
MedWire News: Recombinant apolipoprotein A-I Milano (rApoA-IM) may be a promising therapeutic approach for aortic valve stenosis, a study in rabbits suggests.
The work showed that rApoA-IM administration reversed aortic stenosis in an experimental rabbit model, with the effects being mediated by enhanced cholesterol removal and reduced inflammation and calcification.
An international team led by Juan Badimon (Mount Sinai School of Medicine, New York, USA) tested the impact of rApoA-IM treatment on the progression of aortic stenosis in a rabbit model.
The therapy, which employs a mutant form of apoA-I, has previously been shown to reduce the size of lipid-rich plaques and stabilize vulnerable lesions. Moreover, rApoA-IM treatment has pleiotropic effects including anti-inflammatory actions.
For the present study, Badimon and team fed New Zealand White rabbits a cholesterol-rich diet for 9 months to induce atherosclerosis and aortic valve stenosis. The animals were then randomly assigned to receive rApoA-IM treatment (two intravenous injections at 75 mg/kg, 4 days apart) or an equal volume of saline.
Post-mortem examination of the aortic valves revealed a number of differences between rApoA-IM- and saline-treated rabbits, the researchers report in the European Heart Journal.
Specifically, rApoA-IM therapy was associated with a significant 32% increase in aortic valve area, whereas this parameter was unchanged in the saline group. rApoA-IM-treated animals also showed significantly less thickening, inflammation, and calcification of the leaflets.
In order to investigate the potential mechanisms underlying these effects, the team cultured porcine aortic valve myofibroblasts with oxidized low-density lipoprotein. These showed increased expression of monocyte chemoattractant protein-1, nuclear factor-kB, and alkaline phosphatase.
However, all these effects were significantly inhibited when the cultured cells were pre-exposed to rApoA-IM. In addition, rApoA-IM exposure significantly reduced intracellular cholesterol content.
Badimon and colleagues say that their results have important implications for the management of fibrocalcific aortic valve disease.
“Our observations suggest the potential benefits of high-density lipoprotein/ApoA-I-based interventions,” they write.
“Regression of aortic stenosis, if achieved safely, would transform the clinical approach to this common disease process.”
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By Joanna Lyford