Arterial and venous endothelia display differential functional fractalkine (CX3CL1) expression by angiotensin-II.

OBJECTIVE: Angiotensin-II (Ang-II) promotes the interaction of mononuclear cells with arterioles and neutrophils with postcapillary venules. To investigate the mechanisms underlying this dissimilar response, the involvement of fractalkine (CX(3)CL1) was explored. METHODS AND RESULTS: Enhanced CX(3)CL1 expression was detected in both cremasteric arterioles and postcapillary venules 24 hours after Ang-II intrascrotal injection. Arteriolar leukocyte adhesion was the unique parameter significantly reduced (83%) in animals lacking CX(3)CL1 receptor (CX(3)CR1). Human umbilical arterial and venous endothelial cell stimulation with 1 µmol/L Ang-II increased CX(3)CL1 expression, yet neutralization of CX(3)CL1 activity only significantly inhibited Ang-II-induced mononuclear cell-human umbilical arterial endothelial cell interactions (73%) but not with human umbilical venous endothelial cells. The use of small interfering RNA revealed the involvement of tumor necrosis factor-α in Ang-II-induced CX(3)CL1 upregulation and mononuclear cell arrest. Nox5 knockdown with small interfering RNA or pharmacological inhibition of extracellular signal-regulated kinases1/2, p38 mitogen-activated protein kinase, and nuclear factor-κB also abolished these responses. Finally, when human umbilical arterial endothelial cells were costimulated with Ang-II, tumor necrosis factor-α, and interferon-γ, CX(3)CL1 expression and mononuclear cell adhesiveness were more pronounced than when each stimulus was provided alone. CONCLUSIONS: These results suggest that Ang-II induces functional CX(3)CL1 expression in arterial but not in venous endothelia. Thus, targeting endothelial CX(3)CL1-mononuclear leukocyte CX(3)CR1 interactions may constitute a new therapeutic strategy in the treatment of Ang-II-associated cardiovascular diseases.

Consensus document on treatment of infections in diabetic foot.

Diabetic foot infection, particularly if it is associated to ischaemia,is the most common cause of lower limb amputation, in the general population, of hospital admissions, and a decrease in the quality of life in diabetics. Of all diabetics, 15% of them are going to suffer from a foot infection during their life, with an annual incidence of 1-4%, preceded by a foot ulcer in more than 80% of cases. They are complex infections and the prognosis is influenced by many factors, depending on the ulcer (location, extension, whether chronic or not, previous amputation, ischaemia grade), and the patient (age, renal impairment, time of onset of diabetes, associated comorbidity). All these must be taken into account when establishing its treatment. The infections must be classified according to their severity (mild, moderate-mild, moderatesevere, and severe). Their treatment is complex and must be multidisciplinary and must include debridement, discharge, adequate antibiotic therapy, revascularisation, and treatment of the ulcer. In this consensus document, produced in collaboration with the Spanish Angiology and Vascular Surgery Society (SEACV), the Spanish Society of Internal Medicine (SEMI), the Spanish Chemotherapy Society (SEQ), the Spanish Surgeons Association (AEC), the Spanish Society of Urgent Medicine and Emergencies (INFURG-SEMES) and the Spanish Society of Intensive and Critical Medicine and Coronary Care (SEMICYUC), the guidelines are developed based on the best available evidence on diabetic foot infections, aimed at achieving greater clinical efficacy.

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. Either losartan (an Ang II receptor-1 antagonist, AT(1)) or enalapril (an ACE inhibitor), but not chymostatin (a chymase inhibitor), inhibited Ang I-induced responses. Mast cell degranulation with compound 48/80 (CMP48/80, 1 µg/mL) also induced leucocyte adhesion but this was only weakly affected by the inhibitors. When Ang I and CMP48/80 were co-administered, AT(1B) receptor expression was increased, MCP-4 was found surrounding the vessel wall, and ACE was detected in the endothelium. Ang I + CMP48/80 induced enhanced leucocyte adhesion that was attenuated by losartan, enalapril, enalapril + chymostatin, and cromolyn (a mast cell stabilizer). The use of male mast cell-deficient WBB6F1/J-Kit(w)/Kit(w-v) mice (C57BL/6 background) confirmed these findings. CONCLUSION: In vivo, Ang II is primarily generated by ACE under basal conditions, but in inflammatory conditions, the release of MCP amplifies local Ang II concentrations and the associated inflammatory process. Thus, AT(1) receptor antagonists may be more effective than ACE inhibitors for treating ongoing Ang II-mediated vascular inflammation.