Apolipoprotein A1 Protects Against Necrotic Core Development in Atherosclerotic Plaques: PDZK1-Dependent High-Density Lipoprotein Suppression of Necroptosis in Macrophages

Abstract

BACKGROUND: Atherosclerosis is a chronic disease affecting artery wall and a major contributor to cardiovascular diseases. Large necrotic cores increase risk of plaque rupture leading to thrombus formation. Necrotic cores are rich in debris from dead macrophages. Programmed necrosis (necroptosis) contributes to necrotic core formation. HDL (high-density lipoprotein) exerts direct atheroprotective effects on different cells within atherosclerotic plaques. Some of these depend on the SR-B1 (scavenger receptor class B type 1) and the adapter protein PDZK1 (postsynaptic density protein/Drosophila disc-large protein/Zonula occludens protein containing 1). However, a role for HDL in protecting against necroptosis and necrotic core formation in atherosclerosis is not completely understood. METHODS: Low-density lipoprotein receptor–deficient mice engineered to express different amounts of ApoA1 (apolipoprotein A1), or to lack PDZK1 were fed a high fat diet for 10 weeks. Atherosclerotic plaque areas, necrotic cores, and key necroptosis mediators, RIPK3 (receptor interacting protein kinase 3), and MLKL (mixed lineage kinase domain-like protein) were characterized. Cultured macrophages were treated with HDL to determine its effects, as well as the roles of SR-B1, PDZK1, and the PI3K (phosphoinositide 3-kinase) signaling pathway on necroptotic cell death. RESULTS: Genetic overexpression reduced, and ApoA1 knockout increased necrotic core formation and RIPK3 and MLKL within atherosclerotic plaques. Macrophages were protected against necroptosis by HDL and this protection required SR-B1, PDZK1, and PI3K/Akt pathway. PDZK1 knockout increased atherosclerosis in LDLR KO mice, increasing necrotic cores and phospho-MLKL; both of which were reversed by restoring PDZK1 in BM-derived cells. CONCLUSIONS: Our findings demonstrate that HDL in vitro and ApoA1, in vivo, protect against necroptosis in macrophages and necrotic core formation in atherosclerosis, suggesting a pathway that could be a target for the treatment of atherosclerosis.

High Atherogenic Risk in Ketosis-Prone Type 2 Diabetic Individuals with Ketosis Episodes: A Cross-Sectional Study

“… 29 ApoA1 in vivo prevents necrotic prolapse and necrotic core formation in macrophages in atherosclerosis. 10 In our study, Correlation analysis and multiple linear regression showed that plasma ketones levels were negatively correlated with apoA1. Du et al suggested that TG, TC, and LDL-C were higher in young KPT2D than in T2D.…”

“… 9 HDL has a direct atheroprotective effect on different cells within the atherosclerotic plaque. 10 The body can excrete cholesterol and other lipids by reverse transportation of cholesterol, thus preventing atherosclerosis. ApoA1 is an important component of HDL and plays a key role in the reverse cholesterol transport.…”

Remnant cholesterol is associated with unstable carotid plaque in a neurologically healthy population

“…38 In addition, the ability of ApoA1 to restrain necroptosis in macrophages and inhibit the formation and development of necrotic cores in atherosclerosis may contribute to those mechanisms. 39…”

The dance of macrophage death: the interplay between the inevitable and the microenvironment

“…demonstrated that the HDL treatment of both THP-1 and murine peritoneal macrophages suppressed necroptosis induced by TNF or oxLDL in the presence of the pan-caspases inhibitor. This protective effect was contingent on the HDL receptor SR-B1 and activation of Akt kinase ( 181 ).…”