We demonstrate that hypercholesterolemia induces HDL lipidomic changes, losing phosphatidylcholine-lipid species and gaining cholesteryl esters, and proteomic changes, with losses in cardioprotective proteins. These remodeling changes shifted HDL particles toward a dysfunctional state.

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Objective-Hypercholesterolemia induces endothelial dysfunction, a hallmark of the atherosclerotic process, modulating the expression of key genes in vascular endothelial cells. Methods and Results-By differential display analysis, we have studied the effect of high concentrations of native low density lipoprotein (LDL) on endothelial gene expression. mRNA levels of lysyl oxidase (LOX), an enzyme involved in collagen and elastin cross-linking, were downregulated by LDL treatment in endothelial cells in a dose-and time-dependent manner (80% of inhibition by 180 mg/dL LDL for 24 hours). This reduction of LOX expression was associated with a decrease in LOX activity (40% and 54% of inhibition after 24 and 48 hours of LDL treatment, respectively). LOX mRNA half-life was not modified by LDL, but transcriptional inhibition blocked the effect of LDL. Inhibition of LOX activity by either LDL or ␤-aminopropionitrile, an inhibitor of LOX, increased endothelial permeability (192Ϯ0.19-and 3.37Ϯ0.74-fold, respectively). Interestingly, a reduction in LOX expression (3.5-fold) was observed in vivo in the vascular wall of hypercholesterolemic pigs. Conclusions-These findings suggest that LDL downregulation of LOX could contribute to the endothelial dysfunction caused by hypercholesterolemia, thus contributing to atherosclerotic plaque formation. (Arterioscler Thromb Vasc Biol. 2002;22:1409-1414.)Key Words: endothelial cells Ⅲ low density lipoproteins Ⅲ lysyl oxidase Ⅲ vascular permeability Ⅲ hypercholesterolemia V ascular endothelium acts as a selective barrier, controlling the exchange of macromolecules between blood and the underlying tissues and regulating vascular tone and the thrombogenic/fibrinolytic balance. Endothelial dysfunction associated with hypercholesterolemia is one of the earlier events in the atherosclerotic process. The alteration of endothelial gene expression by high concentrations of LDL leads to a decrease in NO bioavailability [1][2][3] and to an increase in leukocyte recruitment by an induction of adhesion molecule expression. 4 See page 1365It has been reported that atherogenic concentrations of LDL alter the composition and permeability of the endothelial barrier by inducing changes in the basement membrane. 5 Thus, the alteration in endothelial extracellular matrix (ECM) could play a key role in the endothelial dysfunction associated with hypercholesterolemia. One of the key enzymes involved in ECM maturation is lysyl oxidase (LOX). This enzyme, a copper-containing semicarbazide-sensitive amine oxidase, 6 initiates the covalent cross-linking of collagen and elastin that is essential in maintaining ECM structure. LOX oxidatively deaminates peptidyl lysine residues of collagen and elastin, leading to the synthesis of peptidyl aldehydes, which condense spontaneously to form the mature and insoluble ECM. 7 LOX has also been associated with tumor supression 8,9 and chemotaxis, 10 and in the last few years, different LOX isoforms, probably with different substrate specificity and function, have been identif...

Platelets are involved in the clinical presentations of ischemic heart disease. Our objective was to study the antithrombotic effects of a new nitric oxide donor (LA419), a neutral sugar organic nitrate with a protected thiol group in its molecular structure. Animals were randomly distributed in three groups: I) oral administration of LA419 (0.9-1.8-3.6-5 mg/kg/d, 10 days); II) oral administration of standard IS-5-MN (0.9-1.8 mg/kg/d, 10 days); III) non-treated group (control). In catheterized pigs, thrombosis was studied under controlled rheological conditions by radioisotopic evaluation of deposited platelets on damaged vessel wall, placed in an extracorporeal perfusion chamber. Changes in blood pressure, heart rate, and platelet aggregation were evaluated. Results have shown that LA419 significantly decreased thrombus formation according to the degree of vascular damage, and shear rate conditions in a dose-dependent manner (p<0.005), without significant modifications on blood pressure and/or elevation of liver enzymes. In contrast, IS-5-MN only showed a significant reduction on platelet deposition at the high dose, that was associated to hypotension and elevation of liver enzymes. Therefore, we conclude that this new anti-ischemic NO-donor (NOd) LA419 that inhibits platelet function without modifying blood pressure may be a highly efficacious strategy to passivate platelet activation induced by a damaged vessel wall.

Ticagrelor is more efficient than clopidogrel in attenuating myocardial structural and functional alterations post-MI and in improving cardiac healing. These benefits are associated with persistent AMPK and Akt/PKB activation.

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Acute thrombosis is a threat in patients undergoing percutaneous coronary intervention with stent implantation. Our objective was to determine if stent-induced thrombus formation could be inhibited by oral treatment with a thromboxane A(2)/prostaglandin H(2) receptor antagonist (TPr; S18886) as an alternative to standard therapy. Pigs were allocated in the following treatment (p.o) groups: I) clopidogrel (CLOP); II) ASA; III) S18886; IV) ASA+CLOP; and V) placebo-control. Damaged vessel was placed in the Badimon chamber containing a stent and perfused at 212/s. Antithrombotic effects were assessed as (111)In-platelet deposition (PD) in two series (60 and 180 min after drug intake). Fibrin(ogen) deposition, light transmittance aggregometry (LTA; collagen, U46619, and ADP), and bleeding time (BT) were also evaluated. After 60 min S18886 reduced PD < or =48%, 40%, and 35% vs placebo, CLOP-, and ASA-treated animals, respectively (P < 0.05), while ASA+CLOP showed a 58% reduction versus placebo (P < 0.01). After 3 hours, ASA+CLOP decreased PD by 55%, S18886 by 40%, CLOP alone by 28% (P < 0.05), and ASA showed no inhibition versus placebo. Similar effects were found in S18886- and ASA+CLOP-treated animals at both times. Fibrin(ogen) deposition followed the same pattern. Collagen-induced LTA was significantly reduced by ASA, ASA+CLOP, and S18886; S18886 abolished U46619-induced LTA; and, CLOP +/- ASA reduced ADP-induced LTA in a time-dependent manner. TPr blockade did not prolong BT, whereas CLOP +/- ASA significantly did (P < 0.0001). In conclusion, blockade of the TPr provided a fast and potent platelet inhibitory effect in a porcine model of in-stent thrombosis comparable to that of blocking both the ADP receptor and cyclooxygenase activation; in addition, TPr provided a more favorable bleeding risk profile.

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