The Roles of Lipid Oxidation Products and Receptor Activator of Nuclear Factor-κB Signaling in Atherosclerotic Calcification

Abstract

This review focuses on the roles of oxylipids and receptor activator of nuclear factor-kappa B ligand (RANKL) signaling in calcific cardiovascular disease. Both intimal and valvular calcification are closely associated with atherosclerosis, leading investigators to study the role of atherogenic oxidatively modified lipids (oxylipids). Results have identified the molecular signaling through which oxylipids induce osteogenic differentiation and calcification in vascular cells. A surprising concomitant finding was that, in bona fide osteoblasts from skeletal bone, oxylipids have the opposite effect, i.e. inhibiting osteoblastic maturation. This is the basis for the lipid hypothesis of osteoporosis. Oxylipids also induce resorptive osteoclastic cells within the bone environment, raising the question of whether resorptive osteoclasts can be harnessed in the vascular context for cell-based therapy to remove artery wall mineral deposits. The challenge is that, vascular cells produce anti-osteoclastogenic factors, including the soluble decoy receptor for RANKL, possibly accounting for the paucity of resorptive cells and the dominance of mineral in atherosclerotic plaque. These factors may have therapeutic use in osteoclastogenic removal of mineral deposits from arteries.

Upregulation of a Disintegrin and Metalloproteinase With Thrombospondin Motifs-7 by miR-29 Repression Mediates Vascular Smooth Muscle Calcification

“…Various molecular mechanisms have been elucidated, including abnormal calcium or phosphate metabolism, osteogenic reprogramming of VSMCs, apoptosis, oxidative stress and inflammation, and loss of inhibitors of mineralization. [18][19][20][21] However, the understanding of vascular mineralization is far from ideal, and an effective preventive or therapeutic strategy for vascular calcification in atherosclerosis, CRF, and diabetes mellitus is still lacking. Here we reveal a novel underlying mechanism in vascular calcification that involves the miR-29/ ADAMTS-7/COMP axis.…”

Lipoprotein (a) in calcific aortic valve disease: from genomics to novel drug target for aortic stenosis

“…Lp(a) levels are highly correlated with OxPL/apoB levels (r = 0.85), but this correlation is not consistent for all Lp(a) particles, with the highest correlations observed among the smallest, most atherogenic Lp(a) particles (36,37). OxPLs appear to be "danger-associated molecular patterns," which are potent stimulators of innate immunity by interacting with various pattern recognition receptors (12,30,39). In addition, bacterial PC (not as a phospholipid) has molecular identity with PC-containing OxPLs (30).…”

“…First, histopathological evidence demonstrates a more prominent early mineralization phase and a paucity of smooth muscle cells in aortic sclerosis, as compared with vascular atherosclerotic lesions (9). Second, calcification pathways appear to predominate early in valve disease and appear to be independent of the atherosclerotic process, as opposed to vascular disease where calcification develops much later and in parallel with atherosclerosis (12). Third, among individuals undergoing AV replacement for (non-congenital) AS, only 40% have significant coronary artery disease requiring bypass (13), suggesting unique pathological processes.…”

Endoplasmic Reticulum Stress Participates in Aortic Valve Calcification in Hypercholesterolemic Animals

“…In AV calcification, VICs should first be activated by various stimuli to become α-SMA-containing activated VICs, which are then further differentiated into osteoblast-like VICs, 4 whereas vascular smooth muscle cells are already α-SMA positive and can be directly stimulated into osteoblast-like cells. 52 With respect to these important differences between arterial calcification and AV calcification, future studies are required to verify the links between ER stress and arterial calcification in vivo.…”