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-κB ligand signaling in calcific cardiovascular disease. Both intimal and valvular calcifications 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, ie, 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 antiosteoclastogenic factors, including the soluble decoy receptor for receptor activator of nuclear factor-κB ligand, 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.

Fig. 1. The RANKL/RANK/OPG interactions

When RANKL from osteoblasts binds to its receptor, RANK, on the surface of preosteoclastic cells, it induces osteoclastic differentiation. OPG, also from osteoblasts, acts as a soluble decoy receptor for RANKL and, thus, blocks osteoclastic differentiation.

Fig. 2. Working model of the effects of oxidized lipids on vascular and bone calcification based on in vitro and in vivo studies

High levels of serum and tissue oxidized lipids may occur in genetic hyperlipidemia and/or an atherogenic diet. In the artery wall milieu, these oxylipids induce vascular calcification by direct action on SMC or adventitial myofibroblasts and/or through indirect induction of cytokine release from macrophages. Infliximab, an inhibitor of TNF-alpha, blocks this process. In the bone milieu, oxylipids inhibit bone calcification by direct action on osteoblasts and/or through indirect induction of cytokine release from T-lymphocytes.

Fig. 3. Working model of the effects of intermittent PTH on vascular and bone calcification based on in vitro and in vivo studies

In the artery wall, intermittent PTH blocks effects of hyperlipidemia (HL) and/or atherogenic (Ath) diet, also a diabetogenic diet, on induction of vascular calcification. In the bone milieu, oxylipids blunts the anabolic effects of intermittent PTH (as used in therapy for postmenopausal osteoporosis). The apoA-I-mimetic peptide, D-4F, by blocking formation of oxylipids, rescues the effect of PTH on bone. Of note, continuous exposure to PTH, as in clinical hyperparathyroidism, has different, often opposite, effects as intermittent exposure.