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(Circulation Research. 1996;79:871-880.)
© 1996 American Heart Association, Inc.

Articles

Mildly Oxidized LDL Evokes a Sustained Ca²⁺-Dependent Retraction of Vascular Smooth Muscle Cells

Nathalie Auge, Guylene Fitoussi, Jean-Loup Bascands, Marie-Therese Pieraggi, Didier Junquero, Philippe Valet, Jean-Pierre Girolami, Robert Salvayre, Anne Negre-Salvayre

the Laboratory of Biochemistry, Metabolic Disease, INSERM CJF-9206 (N.A., G.F., M.-T.P., R.S., A.N.-S.), Pharmacologie moleculaire et physiopathologie renale, INSERM U388 (J.-L.B., J.-P.G.), and Regulations adrenergiques et adaptation metabolique, INSERM U 317 (P.V.), Institut Louis Bugnard, INSERM/University Paul Sabatier, Toulouse, and Centre de Recherche Pierre Fabre, Maladies cardio-vasculaire I, Castres (D.J.), France.

Correspondence to Dr A. Negre-Salvayre or Prof R. Salvayre, Laboratoire de Biochimie "Maladies Metaboliques," CHU Rangueil, 1 Avenue J. Poulhes, 31054 Toulouse Cedex, France.

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 (200 µg 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 -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.

Key Words: oxidized LDL • calcium • smooth muscle cells • vascular retraction • atherosclerosis

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