Introduction: Pre-clinical studies show high-density lipoproteins (HDL) and apolipoprotein A-I (apoA-I) are atheroprotective in early-stage disease, however, HDL-raising has not yet translated successfully for humans with established plaques.Aim: To determine the efficacy of apoA-I raising on late-stage vs. early-stage lesions and assess changes in key mechanisms of HDL functionality.Methods and Results: In a late-stage plaque model, apoE-/- mice first received high-fat diet (HFD) for 18-weeks before apoA-I was raised for 16 weeks via alternate day apoA-I infusions or lentiviral gene-transfer. In an early-stage model, apoE-/- mice first received HFD for 2 weeks before receiving alternate day apoA-I infusions for 6 weeks. We found apoA-I infusions into mice with late-stage lesions modestly decreased aortic sinus plaque area (8%, p<0.05) and had no effect on thoracic aorta lesions or plaque composition at each site. There were also no changes in adventitial neovascularization, as measured using MicroCT. Constitutive overexpression of apoA-I for 16 weeks by lentivirus also failed to change plaque area or composition in mice with late-stage disease. Conversely, apoA-I infusions in mice with early-stage disease had significantly reduced plaque area (30%), macrophage (51%) and extracellular-lipid content (23%), and increased smooth muscle cell content (34%), p≤0.01. ApoA-I reduced systemic inflammatory markers MCP-1 and SAA in early-stage but not late-stage disease. Ex vivo, HDL from apoA-I-infused mice with late-stage plaque had impaired functionality compared to HDL from apoA-I mice with early-stage disease. HDL from apoA-I mice with late-stage disease was less anti-inflammatory, as measured by VCAM-1 expression, and less anti-apoptotic, as measured by annexinV, via failure to induce anti-apoptotic protein Bcl-xL in human coronary artery endothelial cells. HDL from apoA-I mice with late-stage disease also had attenuated cholesterol efflux capacity in J774A.1 macrophages.Conclusions: In contrast to its beneficial effects in early-stage disease, apoA-I-raising in late-stage disease was associated with a striking attenuation of benefit. This suggests that in advanced atherosclerosis, the protective actions of HDL are compromised.
|Publication status||Published or Issued - 14 Nov 2017|
|Event||AHA Scientific Sessions 2017 - Anaheim, United States|
Duration: 11 Nov 2017 → 15 Nov 2017
|Conference||AHA Scientific Sessions 2017|
|Period||11/11/17 → 15/11/17|