N. Auge et al., MILDLY OXIDIZED LDL EVOKES A SUSTAINED CA2-DEPENDENT RETRACTION OF VASCULAR SMOOTH-MUSCLE CELLS(), Circulation research, 79(4), 1996, pp. 871-880
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 potent
ially involved in arterial spasm and ischemic heart disease. We report
here the role of oxidized LDL in the retraction of vascular smooth mu
scle cells. Mildly oxidized LDL elicited a broad and sustained peak in
cytosolic calcium concentration ([Ca2+](i)) in cultured arterial smoo
th muscle cells. Concomitant with the [Ca2+](i) rise, oxidized LDL evo
ked a sustained and intense retraction of smooth muscle cells, as show
n by the changes in cross-sectional area of single cells. Cell retract
ion 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 e
licited a delayed (12+/-2 hours) and sustained (14+/-2 hours) increase
in isometric tension in deendothelialized arterial rings only, thus s
uggesting a protective role of intact endothelium. When triggered by n
ontoxic doses of oxidized LDL, retraction of cultured cells and the co
ntractile response of aortic rings was reversible, whereas with higher
(toxic) doses (greater than or equal to 200 mu g apoB/mL), cell retra
ction was irreversible and led progressively to detachment and cell de
ath. 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 ox
idized LDL (direct inhibition), eg, by inhibiting calcium influx with
EGTA or the calcium channel blocker nisoldipine or by blocking intrace
llular signaling (at a still-unknown step) by the lipophilic antioxida
nt alpha-tocopherol; and (3) by directly inhibiting myosin light chain
kinase by aphthalene-1-sulfonyl)-1H-hexahydro-1,4-diazepine. In concl
usion, oxidized LDL evoked a sustained and intense calcium-dependent r
etraction of cultured smooth muscle cell, which can be prevented by in
hibiting LDL oxidation or by blocking the intracellular signaling indu
ced by oxidized LDL.