title: Proliferation of macrophages due to the inhibition of inducible nitric oxide synthesis by oxidized low-density lipoproteins.
abstract: Oxidized low-density lipoprotein (ox-LDL) is assumed to be a major causal agent in hypercholesteraemia-induced atherosclerosis. Because the proliferation of lipid-loaden macrophages within atherosclerotic lesions has been described, we investigated the dependence of macrophage proliferation on the inhibition of inducible nitric oxide synthase (iNOS) by hypochlorite oxidized LDL. Ox-LDL induces a dose dependent inhibition of inducible nitric oxide synthesis in lipopolysaccharide-interferon stimulated mouse macrophages (J774.A1) with concomitant macrophage proliferation as assayed by cell counting, tritiated-thymidine incorporation and measurement of cell protein. Native LDL did not influence macrophage proliferation and inducible nitric oxide synthesis. iNOS protein and mRNA was reduced by HOCl-oxidized LDL (0-40 µg/ml) as revealed by immunoblotting and competitive semiquantitative PCR. Macrophage proliferation was increased by the addition of the iNOS inhibitor L-NAME. The addition of ox-LDL to L-NAME containing incubations induced no further statistically significant increase in cell number. Nitric oxide donors decreased ox-LDL induced macrophage proliferation and nitric oxide scavengers restored macrophage proliferation to the initial values achieved by ox-LDL. The decrease of cytosolic DNA fragments in stimulated macrophages incubated with ox-LDL demonstrates that the proliferative actions of ox-LDL are associated with a decrease of NO-induced apoptosis. Our data show that inhibition of iNOS dependent nitric oxide production caused by hypochlorite oxidized LDL enhances macrophage proliferation. This might be a key event in the pathogenesis of atherosclerotic lesions.
authors.affiliation: Institute for Physiology, Section for Vegetative Physiology, CEPP, Medical University Vienna, Schwarzspanierstraße 17, 1090 Vienna, Austria.
authors.forename: Monika
authors.initials: M
authors.lastname: Brunner
authors.affiliation: Institute for Physiology, Section for Vegetative Physiology, CEPP, Medical University Vienna, Schwarzspanierstraße 17, 1090 Vienna, Austria.
authors.forename: Miriam
authors.initials: M
authors.lastname: Gruber
authors.affiliation: Institute for Physiology, Section for Vegetative Physiology, CEPP, Medical University Vienna, Schwarzspanierstraße 17, 1090 Vienna, Austria.
authors.forename: Diethart
authors.initials: D
authors.lastname: Schmid
authors.affiliation: Institute for Physiology, Section for Vegetative Physiology, CEPP, Medical University Vienna, Schwarzspanierstraße 17, 1090 Vienna, Austria.
authors.forename: Halina
authors.initials: H
authors.lastname: Baran
authors.affiliation: Institute for Physiology, Section for Vegetative Physiology, CEPP, Medical University Vienna, Schwarzspanierstraße 17, 1090 Vienna, Austria.
authors.forename: Thomas
authors.initials: T
authors.lastname: Moeslinger
keywords: atherosclerosis; inducible nitric oxide synthase; lipoproteins; macrophages