Retinoid X receptor agonists impair arterial mononuclear cell recruitment through peroxisome proliferator-activated receptor-γ activation.

Mononuclear cell migration into the vascular subendothelium constitutes an early event of the atherogenic process. Because the effect of retinoid X receptor (RXR)α on arterial mononuclear leukocyte recruitment is poorly understood, this study investigated whether RXR agonists can affect this response and the underlying mechanisms involved. Decreased RXRα expression was detected after 4 h stimulation of human umbilical arterial endothelial cells with TNF-α. Interestingly, under physiological flow conditions, TNF-α-induced endothelial adhesion of human mononuclear cells was concentration-dependently inhibited by preincubation of the human umbilical arterial endothelial cells with RXR agonists such as bexarotene or 9-cis-retinoid acid. RXR agonists also prevented TNF-α-induced VCAM-1 and ICAM-1 expression, as well as endothelial growth-related oncogene-α and MCP-1 release. Suppression of RXRα expression with a small interfering RNA abrogated these responses. Furthermore, inhibition of MAPKs and NF-κB pathways were involved in these events. RXR agonist-induced antileukocyte adhesive effects seemed to be mediated via RXRα/peroxisome proliferator-activated receptor (PPAR)γ interaction, since endothelial PPARγ silencing abolished their inhibitory responses. Furthermore, RXR agonists increased RXR/PPARγ interaction, and combinations of suboptimal concentrations of both nuclear receptor ligands inhibited TNF-α-induced mononuclear leukocyte arrest by 60-65%. In vivo, bexarotene dose-dependently inhibited TNF-α-induced leukocyte adhesion to the murine cremasteric arterioles and decreased VCAM-1 and ICAM-1 expression. Therefore, these results reveal that RXR agonists can inhibit the initial inflammatory response that precedes the atherogenic process by targeting different steps of the mononuclear recruitment cascade. Thus, RXR agonists may constitute a new therapeutic tool in the control of the inflammatory process associated with cardiovascular disease.

Cerium dioxide nanoparticles modulate antioxidant defences and change vascular response in the human saphenous vein.

Nanoparticles have a promising future in biomedical applications and knowing whether they affect ex vivo vascular reactivity is a necessary step before their use in patients. In this study, we have evaluated the vascular effect of cerium dioxide nanoparticles (CeO2NPs) on the human saphenous vein in response to relaxing and contractile agonists. In addition, we have measured the protein expression of key enzymes related to vascular homeostasis and oxidative stress. We found that CeO2NPs increased expression of both SOD isoforms, and the consequent reduction of superoxide anion would enhance the bioavailability of NO explaining the increased vascular sensitivity to sodium nitroprusside in the presence of CeO2NPs. The NOX4 reduction induced by CeO2NPs may lead to lower H2O2 synthesis associated with vasodilation through potassium channels explaining the lower vasodilation to bradykinin. In addition, we showed for the first time, that CeO2NPs increase the expression of ACE2 in human saphenous vein, and it may be the cause of the reduced contraction to angiotensin II. Moreover, we ruled out that CeO2NPs have effect on the protein expression of eNOS, sGC, BKca channels and angiotensin II receptors or modify the vascular response to noradrenaline, endothelin-1 and TXA2 analogue. In conclusion, CeO2NPs show antioxidant properties, and together with their vascular effect, they could be postulated as adjuvants for the treatment of cardiovascular diseases.

Myocardial oxidative stress protection by sevoflurane vs. propofol: a randomised controlled study in patients undergoing off-pump coronary artery bypass graft surgery.

CONTEXT: Myocardial oxidative stress plays an essential role in the pathogenesis of ischaemia-reperfusion injury associated with coronary artery bypass grafting (CABG). Both propofol and volatile anaesthetics have been shown to reduce reactive oxygen species in experimental and clinical studies. MAIN OBJECTIVE: To compare the influence of sevoflurane and propofol on myocardial oxidative stress markers (F2-isoprostanes and nitrates/nitrites) in coronary sinus blood samples from patients undergoing off-pump CABG. DESIGN AND SETTING: Randomised controlled clinical study of patients scheduled for off-pump CABG in a tertiary academic university hospital from June 2007 to August 2009. Forty patients consented to enrolment and were assigned to receive either propofol or sevoflurane. INTERVENTIONS: Upon completion of the proximal anastomosis, a retroplegia cannula was inserted in the coronary sinus to obtain blood samples, according to the study protocol. MAIN OUTCOME MEASURES: Markers of lipoperoxidation (F2-isoprostanes) and nitrosative stress (nitrates/nitrites) were measured in coronary sinus blood samples at three time points: after the end of the proximal anastomosis (T1), after completion of all grafts (T2) and 15 min after revascularisation (T3). RESULTS: Of the 40 recruited patients, 38 fully completed the study. In the sevoflurane group (n = 20), concentrations of oxidative stress markers in the coronary sinus remained almost constant and were significantly lower than those in the propofol group (n = 18) at all time points. F2-isoprostanes concentrations were as follows at T1: sevoflurane group 37.2 ±â€Š27.5 pg ml vs. propofol group 170.7 ±â€Š30.9 pg ml [95% confidence interval (CI) 112.16-155.08, P < 0.0001); at T2: sevoflurane group 31.94 ±â€Š24.6 pg ml vs. propofol group 171.6 ±â€Š29.7 pg ml (95% CI 119.78-159.63, P < 0.0001); and at T3: sevoflurane group 23.8 ±â€Š13.0 pg ml vs. propofol group 43.6 ±â€Š31 pg ml (95% CI 2.87-36.63, P = 0.023). CONCLUSION: In patients undergoing off-pump CABG, sevoflurane showed better antioxidative properties than propofol.

Endovascular stent grafting for acute thoracic aortic pathology.

BACKGROUND: Endovascular repair of the thoracic aorta has shown reduced morbidity and mortality compared with open surgery. We describe our experience with endovascular stent grafting in the treatment of acute thoracic aortic pathology. METHODS: From October 2003 to January 2008, 25 patients underwent endovascular stent graft repair of the thoracic aorta. The underlying pathology was a complicated Stanford type B dissection (n = 13), a symptomatic or ruptured thoracic aorta aneurysm (n = 6), a symptomatic penetrating atherosclerotic ulcer (n = 5), or a traumatic aortic injury (n = 1). There were 21 males and four female patients with a mean age of 61.3 years (30-91 years). Routine surveillance included clinical evaluation and contrast-enhanced spiral computed tomography scans before discharge and at 3, 6, and 12 months after the procedure and yearly thereafter. RESULTS: Stent graft placement was technically successful in all patients. There was no intraoperative mortality. Hospital mortality was of two patients (8%). Paraparesis occurred in one patient (4%). Average intensive care unit and hospital stay was 1 and 10 days, respectively. The mean follow-up was 30 months (range, 7-53). Late mortality was in one patient (4%), due to a type A dissection. During the follow-up, four patients (16%) required a second procedure for type I endoleak. CONCLUSIONS: Mortality and morbidity in our small series were low. Close follow-up is mandatory and long-term results have to be awaited.

A novel SDHD mutation associated with neck paraganglioma.

The aim of this study was to describe a previously unreported mutation in the SDHD gene, which has been linked to familial paraganglioma. Clinical data were collected from all members of the family, which had four siblings affected with paraganglioma. For the index patient, genomic DNA extraction from whole blood was performed using the High Pure PCR Template Preparation kit. The nucleotide sequence in the index patient revealed a deletion in the SDHD gene, c.165_169 + 14del. The loss of nucleotides in the DNA led to production of an anomalous protein. RNA analysis showed the absence of exon 2 in the sequence that corresponded to the mRNA from the index case. Genetic testing of this deletion was extended to the symptomatic and asymptomatic brothers and sisters of the index patient and other family members at risk. The deletion was detected in both symptomatic brothers, in accordance with their phenotype, but not in the asymptomatic sister. In the other asymptomatic brother (II.7) the deletion was detected and magnetic resonance angiography revealed the vascular characteristics of two tumors in both carotid bifurcations. Thus, we report a novel punctual mutation in the SDHD gene, which is related to familial paraganglioma: the deletion was c.165_169 + 14del.

Surgical treatment of aneurysm of right aortic arch with cervical aorta.

A patient with a cervical aorta and an aneurysm of a right sided aortic arch was treated without cardiopulmonary bypass by ascending to distal descending aorta bypass grafting, excision of the aneurysm and its transverse connection to the descending aorta and of the cervical segment of the aorta, and connection of the right subclavian artery to the ascending aorta. The clinical result is excellent after 9 years of follow-up.