Minimally modified low density lipoprotein-induced inflammatory responses in endothelial cells are mediated by cyclic adenosine monophosphate.

Abstract

We have previously shown that minimally oxidized LDL (MM-LDL) activated endothelial cells to increase their interaction with monocytes but not neutrophils, inducing monocyte but not neutrophil binding and synthesis of monocyte chemotactic protein-i and monocyte colony-stimulating factor (M-CSF). In the present studies we have examined the signaling pathways by which this monocyte-specific response is induced. Both induction of monocyte binding and mRNA levels for M-CSF by MM-LDL were not inhibited in protein kinase C-depleted endothelial cells. A number of our studies indicate that cAMP is the second messenger for the effects of MM-LDL cited above. Incubation of endothelial cells with MM-LDL caused a 173% increase in intracellular cAMP levels. Agents which increased cAMP levels, including cholera toxin, pertussis toxin, dibutyryl cAMP, and isoproterenol mimicked the actions of MM-LDL. Agents which elevated cAMP were also shown to activate NFKB, suggesting a role for this transcription factor in activation of monocyte-endothelial interactions. Although endothelial leukocyte adhesion molecule (ELAM) mRNA synthesis can be regulated by NFKB, ELAM was not expressed and ELAM mRNA was only slightly elevated in response to MM-LDL. We present evidence that induction of neutrophil binding by LPS is actually suppressed by agents that elevated cAMP levels. (J. Clin. Invest. 1993. 92:471-478.)

Oxidation-dependent effects of oxidized LDL: proliferation or cell death

“…The whole oxLDL induced differentiation (Parhami et al, 1993), gene expression (Han et al, 1997), cytokine production (Thomas et al, 1994;Lipton et al, 1995), inhibition of the macrophage motility (Quinn et al, 1985), cytotoxicity (Dimmeler et al, 1997), inhibition of the nitric oxide-induced vasodilatation (Liao et al, 1995;Goss et al, 1997), and mitogenicity (Auge et al, 1995;Auge et al, 1996;Chai et al, 1996). Different components of oxLDL might play roles in these various biological activities.…”

“…Different investigators utilized different methods to oxidize LDL and present different criteria for LDL oxidation. For example, Bjorkerud and Bjorkerud (1996) and Auge, et al (1995) utilized UV-or Fe-mediated oxidation to prepare oxLDL while others used cell- (Quinn et al, 1985), enzyme- (Parhami et al, 1993) or copper- (Chai et al, 1996;Hardwick et al, 1996) mediated methods. They used different concentration and conditions of catalyst, and presented malondialdehyde (MDA) formation by thiobarbituric acid-reactive substances (TBARS) assay as a criterion for the oxidation extent.…”

Biochemistry and pathology of radical-mediated protein oxidation

“…A myriad of potentially pathogenic activities have been attributed to LDL and to some of its components at various poorly defined stages of oxidation (e.g. [267]). The possible roles of the oxidized protein components need to be considered.…”

Detection of HOCl-mediated protein oxidation products in the extracellular matrix of human atherosclerotic plaques

“…Both covalent modification and oxidation of low-density lipoproteins (LDLs), a major source of the lipids present in plaque, are known to trigger degeneration in cellular control over LDL uptake, leading to lipid accumulation and the formation of macrophage-derived foam cells [5][6][7][8]. It is also well established that oxidatively modified LDLs can have other effects, including effects on endothelial cell viability, cytokine expression and smooth-muscle cell proliferation ( [9][10][11], reviewed in [3]). …”