Mildly Oxidized LDL Evokes a Sustained Ca ²⁺ -Dependent Retraction of Vascular Smooth Muscle Cells

Abstract

Oxidized low density lipoprotein (LDL) is thought to play a major role in atherogenesis. Atherosclerotic arteries exhibit structural changes associated with profound alterations in vascular tone that are potentially involved in arterial spasm and ischemic heart disease. We report here the role of oxidized LDL in the retraction of vascular smooth muscle cells. Mildly oxidized LDL elicited a broad and sustained peak in cytosolic calcium concentration ([Ca2+]i) in cultured arterial smooth muscle cells. Concomitant with the [Ca2+]i rise, oxidized LDL evoked a sustained and intense retraction of smooth muscle cells, as shown by the changes in cross-sectional area of single cells. Cell retraction was dependent on time, the concentration of oxidized LDL, and the level of LDL oxidation (native LDL induced neither a significant [Ca2+]i rise nor cell retraction). Oxidized LDL but not native LDL also elicited a delayed (12 +/- 2 hours) and sustained (14 +/- 2 hours) increase in isometric tension in deendothelialized arterial rings only, thus suggesting a protective role of intact endothelium. When triggered by nontoxic doses of oxidized LDL, retraction of cultured cells and the contractile response of aortic rings was reversible, whereas with higher (toxic) doses (> or = 200 micrograms apoB/mL), cell retraction was irreversible and led progressively to detachment and cell death. Cell retraction can be prevented in three ways: (1) by inhibiting LDL oxidation with supplements of antioxidants (indirect inhibition); (2) by blocking the pathogenic intracellular signaling elicited by oxidized LDL (direct inhibition), eg, by inhibiting calcium influx with EGTA or the calcium channel blocker nisoldipine or by blocking intracellular signaling (at a still-unknown step) by the lipophilic antioxidant alpha-tocopherol; and (3) by directly inhibiting myosin light chain kinase by 1-(5-chloronaphthalene-1-sulfonyl)-1H-hexahydro-1, 4-diazepine. In conclusion, oxidized LDL evoked a sustained and intense calcium-dependent retraction of cultured smooth muscle cell, which can be prevented by inhibiting LDL oxidation or by blocking the intracellular signaling induced by oxidized LDL.

A redox-sensitive pathway mediates oxidized LDL-induced downregulation of insulin-like growth factor-1 receptor

“…It has been reported that OxLDL stimulates a variety of signal pathways in several cell types, including the sphingomyelin-ceramide pathway (38), Ca-dependent signaling (39,40), protein kinase C (41), tyrosine kinase-dependent activation of ERK (19,20), and a p38 MAPK pathway (11). OxLDL can also activate PPAR␥-inducible gene expression, because the oxidized fatty acids contained in OxLDL, 13-hydroperoxyoctadecadienoic acid (13-HPODE) and 13-(S)-hydroxyoctadecadienoic acid (13-HODE), are ligands for PPAR␥ (25).…”

“…by guest, on May 2, 2019 www.jlr.org Downloaded from move EDTA, then the nLDL fraction (0.2 mg/ml, diluted in PBS) was incubated with 5 mol/l CuSO 4 at 37 Њ C for 3 h. The reaction was stopped by adding EDTA (final concentration, 0.25 mmol/l). It is likely that such OxLDL has considerable amounts of peroxidized lipids.…”

Large-Artery Elastic Properties in Young Men

“…endothelial dysfunction, or by promoting smooth muscle cell proliferation. 23,[25][26][27][28] A recent study by Ramsey et al 29 showed that arterial distensibility is controlled by normal endothelium in healthy subjects.…”

Lysophosphatidylcholine Decreases Delayed Rectifier K+ Current in Rabbit Coronary Smooth Muscle Cells.

“…Especially, oxidative modification of LDL is a key factor for progression of atherosclerosis [19], and in vitro application of oxidized LDL mimicked the abnormal vascular reactivity, which was seen in atherosclerotic artery [4,9,13]. Several studies suggested that LPC might be the active component mediating the in vitro effect of oxidized LDL on vascular contraction.…”