Abstract 15785: Strikingly Different Atheroprotective Effects of Apolipoprotein A-I in Early-Stage Versus Late-Stage Atherosclerosis
Background: HDL has shown consistent benefit on early atherosclerosis in animals; however, this has not translated into successful therapy for humans with established disease. We aimed to investigate if there were differences in the effectiveness of HDL-raising (via apoA-I infusion or gene therapy) between animals with late-stage established atherosclerosis versus early-stage fatty streaks.
Protocol: In a late-stage plaque model, 8 week-old apoE -/- mice received a high fat diet (HFD) for a total of 32 weeks. Following 18 weeks of HFD, apoA-I was raised for 16 weeks via two strategies: 1) human apoA-I infusions of 40mg/kg intravenously 2-3 times/week, or 2) human apoA-I lentiviral gene-transfer. In an early-stage model, 4 week-old apoE -/- mice received HFD for a total of 8 weeks. Following 2 weeks of HFD, mice received infusions of human apoA-I for 6 weeks.
Results: ApoA-I infusions into mice with late-stage atherosclerosis only modestly decreased aortic sinus lesion area by 7.7% (p≤0.05), but did not change descending aorta lesion area nor plaque composition at either site. Furthermore, there was no change in plaque area or adventitial neovascularisation in the descending aorta, as assessed using Micro-CT. Consistent with this, constitutive overexpression of apoA-I using lentiviral gene transfer had no effect on plaque area or composition in mice with established atherosclerosis, despite higher apoA-I levels. Conversely, infusions of apoA-I into mice with early-stage lesions decreased aortic sinus lesion area by 30.2% (p≤0.0001), plaque macrophages by 51.2% (p≤0.01) and extracellular-lipid by 22.8% (p≤0.01); and increased smooth muscle cell content by 34.4% (p≤0.01). Two inflammatory proteins, MCP-1 and SAA, were reduced by 29.6% and 18.1% respectively (p≤0.05) in early-stage but not in late-stage disease.
Conclusion: In contrast to its beneficial effects in early stage atherosclerosis, HDL-raising in late-stage disease was associated with a striking attenuation of benefit on plaque size, plaque composition and inflammatory markers. In advanced atherosclerosis, the atheroprotective functions of HDL may be less effective, possibly due to impaired capacity to inhibit inflammation or promote cholesterol efflux.
- © 2013 by American Heart Association, Inc.