Enhanced atheroprotection and lesion remodelling by targeting the foam cell and increasing plasma cholesterol acceptors

Abstract

Aims: Atherosclerosis development can be ameliorated by promoting reverse cholesterol transport (RCT) from arteries. The process involves cholesterol efflux from foam cells to extracellular acceptors such as apolipoprotein A-I (apoA-I) and high-density lipoprotein (HDL) that mediate transport to the liver. Perilipin-2 (PLIN2) is a lipid droplet (LD)-associated protein that in macrophages facilitates cholesterol storage and prevents efflux. We hypothesized that atheroprotection would be enhanced by concurrently targeting PLIN2 to increase the efflux capacity of foam cells and increasing plasma apoA-I and HDL.

Methods and results: PLIN2-knockout and wild-type mice lacking apolipoprotein E (PLIN2(-/-)/apoE(-/-) and PLIN2(+/+)/apoE(-/-)) were treated with a helper-dependent adenoviral vector encoding human apoA-I (HDAd-AI) or with control empty vector. Treatment with HDAd-AI increased hepatic apoA-I production, plasma apoA-I and HDL-cholesterol (HDL-C), and apoA-I deposition in lesions to a similar extent in PLIN2(-/-)/apoE(-/-) and PLIN2(+/+)/apoE(-/-) mice. However, atherosclerosis development at the aortic sinus was considerably lower in HDAd-AI-treated PLIN2(-/-)/apoE(-/-) mice. A more stable lesion phenotype, with increased collagen content, was primarily associated to treatment with HDAd-AI, but was enhanced under PLIN2 deficiency. PLIN2 deficiency and apoA-I cumulatively reduced LDs and cholesterol ester content in cultured macrophages. Neutral lipid in atheroma was significantly reduced in HDAd-AI-treated PLIN2(-/-)/apoE(-/-) mice, and RCT from macrophages to feces was enhanced in PLIN2(-/-) macrophages.

Conclusion: These studies demonstrate a mutually beneficial relationship between PLIN2 deficiency and elevated apoA-I/HDL-C in preventing atherosclerosis development. The data support that targeting foam cell components to mobilize cholesterol may be a promising strategy to enhance the atheroprotection of plasma cholesterol acceptors.

Keywords: Apolipoprotein A-I; Atherosclerosis; Foam cell; Lipid droplet; Perilipin-2; Reverse cholesterol transport.