Pitavastatin Differentially Modulates MicroRNA-Associated Cholesterol Transport Proteins in Macrophages.

There is emerging evidence identifying microRNAs (miRNAs) as mediators of statin-induced cholesterol efflux, notably through the ATP-binding cassette transporter A1 (ABCA1) in macrophages. The objective of this study was to assess the impact of an HMG-CoA reductase inhibitor, pitavastatin, on macrophage miRNAs in the presence and absence of oxidized-LDL, a hallmark of a pro-atherogenic milieu. Treatment of human THP-1 cells with pitavastatin prevented the oxLDL-mediated suppression of miR-33a, -33b and -758 mRNA in these cells, an effect which was not uniquely attributable to induction of SREBP2.

Characterization of a cellular denitrase activity that reverses nitration of cyclooxygenase.

Protein 3-nitrotyrosine (3-NT) formation is frequently regarded as a simple biomarker of disease, an irreversible posttranslational modification that can disrupt protein structure and function. Nevertheless, evidence that protein 3-NT modifications may be site selective and reversible, thus allowing for physiological regulation of protein activity, has begun to emerge. We have previously reported that cyclooxygenase (COX)-1 undergoes heme-dependent nitration of Tyr(385), an internal and catalytically essential residue.

Antioxidants condition pleiotropic vascular responses to exogenous H(2)O(2): role of modulation of vascular TP receptors and the heme oxygenase system.

Aims: Hydrogen peroxide (H(2)O(2)), a nonradical oxidant, is employed to ascertain the role of redox mechanisms in regulation of vascular tone. Where both dilation and constriction have been reported, we examined the hypothesis that the ability of H(2)O(2) to effect vasoconstriction or dilation is conditioned by redox mechanisms and may be modulated by antioxidants.

Results: Exogenous H(2)O(2) (0.

Inducible nitric oxide synthase gene deletion exaggerates MAPK-mediated cyclooxygenase-2 induction by inflammatory stimuli.

Cyclooxygenase (COX)-2 and inducible nitric oxide (NO) synthase (iNOS) are responsive to a wide array of inflammatory stimuli, have been localized to vascular smooth muscle cells (SMCs), and are intimately linked to the progression of vascular disease, including atherosclerotic lesion formation. We and others have shown that the production and subsequent impact of COX products appear to be correlative with the status of NO synthesis. This study examined the impact of inflammation-driven NO production on COX-2 expression in SMCs.

Silent Partner in Blood Vessel Homeostasis? Pervasive Role of Nitric Oxide in Vascular Disease.

The endothelium generates powerful mediators that regulate blood flow, temper inflammation and maintain a homeostatic environment to prevent both the initiation and progression of vascular disease. Nitric oxide (NO) is arguably the single most influential molecule in terms of dictating blood vessel homeostasis. In addition to direct effects associated with altered NO production (e.

Dual pathways of carbon monoxide-mediated vasoregulation: modulation by redox mechanisms.

Rationale: Vascular tissues produce carbon monoxide (CO) via HO-dependent and HO-independent mechanisms; the former in tandem with biliverdin and iron and the latter as a lone product. CO has been shown to function as both a vasoconstrictor and vasodilator; however, factors that dictate the vasoregulatory phenotype of this gas are unknown.

Objective: We investigated whether CO-mediated vasoconstriction is mechanistically linked to enhanced reactive oxygen species production that masks vasodilatory pathways.

Pitavastatin suppresses mitogen activated protein kinase-mediated Erg-1 induction in human vascular smooth muscle cells.

Statins have been demonstrated to elicit a broad range of cellular events resulting in an attenuation of the inflammatory response and enhanced protection to the components of the vessel wall. The present study was designed to examine the effect of pitavastatin on pathways associated with the proinflammatory gene, early growth response (Egr)-1, in human vascular smooth muscle cells. Pretreatment with pitavastatin resulted in a dose-dependent reduction in Egr-1 protein and suppressed Egr-1 mRNA expression in response to phorbol 12-myristate 13-acetate (PMA).

Inflammation at the molecular interface of atherogenesis: an anthropological journey.

Despite the multifactorial nature of atherosclerosis, substantial evidence has established inflammation as an often surreptitious, yet critical and unifying driving force which promotes disease progression. To this end, research has defined molecular networks initiated by cytokines, growth factors and other pro-inflammatory molecules which promote hallmarks of atherosclerosis such as endothelial dysfunction, macrophage infiltration, LDL oxidation, cell proliferation and thrombosis. Although commonly associated with risk factors such as dyslipidemia, diabetes and hypertension, the global etiology of atherosclerosis may be alternatively attributed to underlying anthropological pressures.

Carbon monoxide and biliverdin prevent endothelial cell sloughing in rats with type I diabetes.

Hyperglycemia has been linked to increased oxidative stress, a resultant endothelial cell dysfunction, and, ultimately, apoptosis. Heme oxygenases (HO-1/HO-2) and the products of their activity, biliverdin/bilirubin and carbon monoxide (CO), play a physiological role in the vascular system. The effects of heme-mediated HO-1 induction, CO, and biliverdin on urinary 8-epi-isoprostane PGF(2alpha) and endothelial cell sloughing were examined in an animal model of streptozotocin (STZ)-induced diabetes.

Nitric oxide synthesis inhibition promotes renal production of carbon monoxide.

We tested the hypothesis that the status of NO synthesis influences the renal heme-heme oxygenase system. Studies were conducted in untreated rats and rats treated with the NO synthesis inhibitor N(G)-nitro-L-arginine methyl ester for 2 days. Treated and untreated rats were contrasted in terms of renal expression of heme oxygenase-1 and -2, renal carbon monoxide (CO)-generating activity, and urinary CO concentration and excretion rate.