Contributions of ACE and mast cell chymase to endogenous angiotensin II generation and leucocyte recruitment in vivo.

Aims: In vitro studies suggest that mast cell chymase (MCP) is more important than angiotensin-converting enzyme (ACE) for generating angiotensin II (Ang II) within the cardiovascular system. We investigated in vivo the relative contributions of ACE and MCP to leucocyte recruitment induced by endogenously generated Ang II.

Methods And Results: Exposure of the murine cremasteric microcirculation of C57BL/6 mice to Ang I (100 nM for 4 h) induced leucocyte-endothelium interactions.

p19(ARF) deficiency reduces macrophage and vascular smooth muscle cell apoptosis and aggravates atherosclerosis.

Objectives: The goal of this study was to investigate the role in atherosclerosis of the tumor suppressor protein ARF (human p14(ARF), mouse p19(ARF)) encoded by the CDKN2A gene.

Background: Atherosclerosis is characterized by excessive proliferation and apoptosis, 2 cellular processes regulated by CDKN2A. Although recent genome-wide association studies have linked atherosclerotic diseases to a genomic region in human chromosome 9p21 near the CDKN2A locus, the mechanisms underlying this gene-disease association remain undefined, and no causal link has been established between CDKN2A and atherosclerosis.

Control of cell proliferation in atherosclerosis: insights from animal models and human studies.

Excessive hyperplastic cell growth within occlusive vascular lesions has been recognized as a key component of the inflammatory response associated with atherosclerosis, restenosis post-angioplasty, and graft atherosclerosis after coronary artery bypass. Understanding the molecular mechanisms that regulate arterial cell proliferation is therefore essential for the development of new tools for the treatment of these diseases. Mammalian cell proliferation is controlled by a large number of proteins that modulate the mitotic cell cycle, including cyclin-dependent kinases, cyclins, and tumour suppressors.

Atherosclerosis development in apolipoprotein E-null mice deficient for CD69.

Aims: Atherosclerosis is a chronic inflammatory disease regulated by immune mechanisms. CD69 is a cell surface receptor rapidly induced after leukocyte activation at sites of chronic inflammation. Genetic disruption of CD69 in the mouse aggravates collagen-induced arthritis (CIA), and partial depletion of CD69-expressing cells with anti-CD69 monoclonal antibody (mAb) prevents CIA development in wild-type mice, suggesting that this receptor negatively modulates immune and inflammatory responses.

CXCR2 blockade impairs angiotensin II-induced CC chemokine synthesis and mononuclear leukocyte infiltration.

Objective: Angiotensin II (Ang-II) and mononuclear leukocytes are involved in atherosclerosis. This study reports the inhibition of Ang-II-induced mononuclear cell recruitment by CXCR2 antagonism and the mechanisms involved.

Methods And Results: Ang-II (1 nmol/L, i.

A critical role for TNFalpha in the selective attachment of mononuclear leukocytes to angiotensin-II-stimulated arterioles.

Angiotensin II (Ang-II) exerts inflammatory activity and is involved in different cardiovascular disorders. This study has evaluated the involvement of tumor necrosis factor alpha (TNFalpha) in the leukocyte accumulation elicited by Ang-II. Ang-II (1 nM intraperitoneally in rats) induced TNFalpha release at 1 hour followed by neutrophil and mononuclear cell recruitment.

Olive oil-based lipid emulsion's neutral effects on neutrophil functions and leukocyte-endothelial cell interactions.

Background: Infection remains a drawback of parenteral nutrition (PN), probably related, among other factors, to immunosuppressive effects of its lipid component. Newer preparations may have lesser immunosuppressive impact. This study examines the effects of an olive oil-based lipid emulsion (long-chain triacylglycerols-monounsaturated fatty acids [LCT-MUFA]; ClinOleic) on various functions of human neutrophils in vitro and on rat leukocyte-endothelial cell interactions in vivo compared with LCT (Intralipid) and 50% LCT-50% medium-chain triacylglycerols (MCT; Lipofundin) mixture.

Angiotensin II-induced mononuclear leukocyte interactions with arteriolar and venular endothelium are mediated by the release of different CC chemokines.

Angiotensin II (Ang-II) is associated with atherogenesis and arterial subendothelial mononuclear leukocyte infiltration. We have demonstrated that Ang-II causes the initial attachment of mononuclear cells to the arteriolar endothelium. We now report on the contribution of CC chemokines to this response.

A small molecule, orally active, alpha4beta1/alpha4beta7 dual antagonist reduces leukocyte infiltration and airway hyper-responsiveness in an experimental model of allergic asthma in Brown Norway rats.

alpha(4)beta(1) and alpha(4)beta(7) integrins are preferentially expressed on eosinophils and mononuclear leukocytes and play critical roles in their recruitment to inflammatory sites. We investigated the effects of TR14035, a small molecule, alpha(4)beta(1)/alpha(4)beta(7) dual antagonist, in a rat model of allergic asthma. Actively sensitized rats were challenged with aerosol antigen or saline on day 21, and the responses evaluated 24 and 48-h later.

Effect of boldine, secoboldine, and boldine methine on angiotensin II-induced neurtrophil recruitment in vivo.

Angiotensin-II (Ang-II) has inflammatory activity and is involved in different diseases associated with the cardiovascular system. This study has evaluated the effect of boldine (B), and two phenanthrene alkaloids semisynthesized by us, secoboldine (SB) and boldine methine (BM), on Ang-II-induced neutrophil recruitment. Intraperitoneal administration of 1 nM Ang-II induced significant neutrophil accumulation, which was maximal at 4-8 h.

L-NAME induces direct arteriolar leukocyte adhesion, which is mainly mediated by angiotensin-II.

Objective: Acute inhibition (1 h) of nitric oxide synthase (NOS) with L-NAME causes leukocyte recruitment in the rat mesenteric postcapillary venules that is angiotensin-II (Ang-II) dependent. Since 4-h exposure to Ang-II provokes arteriolar leukocyte adhesion, this study was designed to investigate whether subacute (4-h) NOS inhibition also causes this effect.

Methods: Rats were intraperitoneally injected with saline, L-NAME, or 1H-[1,2,4]-oxidazolol-[4,3-a]-quinoxalin-1-one (ODQ).

Effect of boldine, secoboldine, and boldine methine on angiotensin II-induced neutrophil recruitment in vivo.

Angiotensin-II (Ang-II) has inflammatory activity and is involved in different diseases associated with the cardiovascular system. This study has evaluated the effect of boldine (B), and two phenanthrene alkaloids semisynthesized by us, secoboldine (SB) and boldine methine (BM), on Ang-II-induced neutrophil recruitment. Intraperitoneal administration of 1 nM Ang-II induced significant neutrophil accumulation, which was maximal at 4-8 h.

Erythromycin exerts in vivo anti-inflammatory activity downregulating cell adhesion molecule expression.

1. Macrolides have long been used as anti-bacterial agents; however, there is some evidence that may exert anti-inflammatory activity. Therefore, erythromycin was used to characterize the mechanisms involved in their in vivo anti-inflammatory activity.

Angiotensin II induces neutrophil accumulation in vivo through generation and release of CXC chemokines.

Background: Angiotensin II (Ang II) is implicated in the development of cardiac ischemic disorders in which prominent neutrophil accumulation occurs. Ang II can be generated intravascularly by the renin-angiotensin system or extravascularly by mast cell chymase. In this study, we characterized the ability of Ang II to induce neutrophil accumulation.

Direct evidence of leukocyte adhesion in arterioles by angiotensin II.

Although leukocytes adhere in arteries in various vascular diseases, to date no endogenous proinflammatory molecule has been identified to initiate leukocyte adhesion in the arterial vasculature. This study was undertaken to assess angiotensin II (Ang II)-induced leukocyte adhesion in arterioles in vivo. Rats received intraperitoneal injections of Ang II; 4 hours later, leukocyte recruitment in mesenteric microcirculation was examined using intravital microscopy.