Interventional hepatic apoC-III knockdown improves atherosclerotic plaque stability and remodeling by triglyceride lowering.

Autor:	Ramms B; Department of Medicine, University of California, San Diego, La Jolla, California, USA.; Department of Chemistry, Biochemistry I, Bielefeld University, Bielefeld, Germany., Patel S; Department of Medicine, University of California, San Diego, La Jolla, California, USA., Sun X; Department of Medicine, University of California, San Diego, La Jolla, California, USA.; Department of Pharmacology, Mays Cancer Center, Transplant Center, University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA., Pessentheiner AR; Department of Medicine, University of California, San Diego, La Jolla, California, USA., Ducasa GM; Department of Medicine, University of California, San Diego, La Jolla, California, USA., Mullick AE; Ionis Pharmaceuticals, Carlsbad, California, USA., Lee RG; Ionis Pharmaceuticals, Carlsbad, California, USA., Crooke RM; Ionis Pharmaceuticals, Carlsbad, California, USA., Tsimikas S; Department of Medicine, University of California, San Diego, La Jolla, California, USA.; Ionis Pharmaceuticals, Carlsbad, California, USA., Witztum JL; Department of Medicine, University of California, San Diego, La Jolla, California, USA., Gordts PL; Department of Medicine, University of California, San Diego, La Jolla, California, USA.; Glycobiology Research and Training Center, University of California, San Diego, La Jolla, California, USA.
Jazyk:	angličtina
Zdroj:	JCI insight [JCI Insight] 2022 Jul 08; Vol. 7 (13). Date of Electronic Publication: 2022 Jul 08.
DOI:	10.1172/jci.insight.158414
Abstrakt:	Apolipoprotein C-III (apoC-III) is a critical regulator of triglyceride metabolism and correlates positively with hypertriglyceridemia and cardiovascular disease (CVD). It remains unclear if therapeutic apoC-III lowering reduces CVD risk and if the CVD correlation depends on the lipid-lowering or antiinflammatory properties. We determined the impact of interventional apoC-III lowering on atherogenesis using an apoC-III antisense oligonucleotide (ASO) in 2 hypertriglyceridemic mouse models where the intervention lowers plasma triglycerides and in a third lipid-refractory model. On a high-cholesterol Western diet apoC-III ASO treatment did not alter atherosclerotic lesion size but did attenuate advanced and unstable plaque development in the triglyceride-responsive mouse models. No lesion size or composition improvement was observed with apoC-III ASO in the lipid-refractory mice. To circumvent confounding effects of continuous high-cholesterol feeding, we tested the impact of interventional apoC-III lowering when switching to a cholesterol-poor diet after 12 weeks of Western diet. In this diet switch regimen, apoC-III ASO treatment significantly reduced plasma triglycerides, atherosclerotic lesion progression, and necrotic core area and increased fibrous cap thickness in lipid-responsive mice. Again, apoC-III ASO treatment did not alter triglyceride levels, lesion development, and lesion composition in lipid-refractory mice after the diet switch. Our findings suggest that interventional apoC-III lowering might be an effective strategy to reduce atherosclerosis lesion size and improve plaque stability when lipid lowering is achieved.
Databáze:	MEDLINE
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