[Show abstract][Hide abstract] ABSTRACT: Background and aimsDifferent adipokines have been associated with atherosclerotic plaque rupture and cardiovascular events, such as acute ischemic stroke (AIS). However, the potential role of these molecules in post-ischemic brain injury remains largely unknown.Methods and methodsWe performed a sub-study analysis on non-obese patients with first atherothrombotic stroke (n=35) from a recently published prospective cohort. Primary end-point was to investigate the predictive value of serum leptin/adiponectin ratio on neurological recovery at 90-day after AIS. The secondary end-point was the predictive value of serum adipokine levels of clinical and radiological outcomes at a shorter follow up (at day 1 and 7 after AIS). The radiological evaluation included ischemic lesion volume and hemorrhagic transformation (HT). The clinical examination was based on National Institutes of Health Stroke Scale (NIHSS) and modified Rankin scale (mRS).ResultsAt day 1 after AIS, serum leptin and leptin/adiponectin ratio were increased and inversely correlated with both radiological and clinical parameters at all follow up time points. Once identified the best cut-off points by receiver operator curve (ROC) analysis, risk analysis showed that higher circulating leptin improved neurological recovery at day 90. In addition, leptin/adiponectin ratio maintained statistical significance after adjustment for age, gender and thrombolysis, also predicting the occurrence of HT in the first 7 days after AIS (adjusted OR 0.15 [95% CI 0.03-0.83); p=0.030]).Conclusions
Higher leptin/adiponectin ratio at day 1 predicted better neurological outcomes in patients with atherothrombotic AIS and might be potentially useful as a prognostic biomarker of the disease.This article is protected by copyright. All rights reserved.
European Journal of Clinical Investigation 09/2015; 45(11). DOI:10.1111/eci.12538 · 2.73 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Auto-antibodies to apolipoprotein A-1 (anti-apoA-1 IgG) were shown to promote inflammation and atherogenesis, possibly through innate immune receptors signalling. Here, we aimed at investigating the role of Toll-like receptors (TLR) 2 and 4 on anti-apoA-1 IgG-induced atherosclerotic plaque vulnerability, myocardial necrosis and mortality in mice. Adult male apolipoprotein E knockout (ApoE)-/- (n=72), TLR2-/-ApoE-/- (n=36) and TLR4-/-Apo-/- (n=28) mice were intravenously injected with 50 µg/mouse of endotoxin-free polyclonal anti-apoA-1 IgG or control isotype IgG (CTL IgG) every two weeks for 16 weeks. Atherosclerotic plaque size and vulnerability were assessed by histology. Myocardial ischaemia and necrosis, respectively, were determined by electrocardiographic (ECG) changes assessed by telemetry and serum troponin I (cTnI) measurements. Impact on survival was assessed by Kaplan-Meier analyses. In ApoE-/- mice, anti-apoA-1 IgG passive immunisation enhanced histological features of atherosclerotic plaque vulnerability (increase in neutrophil and MMP-9 and reduction in collagen content), induced a substantial cTnI elevation (p=0.001), and increased mortality rate by 23 % (LogRank, p=0.04) when compared to CTL IgG. On a subgroup of ApoE-/- mice equipped with telemetry (n=4), a significant ST-segment depression was noted in anti-apoA-1 IgG-treated mice when compared to CTL IgG recipients (p< 0.001), and an acute ST-segment elevation myocardial infarction preceding mouse death was observed in one case. The deleterious effects of anti-apoA-1 IgG on atherosclerotic plaque vulnerability, myocardial necrosis and death were partially reversed in TLR2-/-ApoE-/- and TLR4-/-ApoE-/- backgrounds. In conclusion, anti-apoA-1 auto-antibodies seem to be active mediators of atherosclerotic plaque vulnerability, myocardial necrosis, and mortality in mice through TLR2- and TLR4-mediated pathways.
Thrombosis and Haemostasis 04/2015; 114(20150416). DOI:10.1160/TH14-12-1039 · 4.98 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background
After an acute ischemic stroke (AIS), several inflammatory biomarkers have been investigated, but their predictive role on functional recovery remains to be validated. Here, we investigated the prognostic relevance of biomarkers related to atherosclerotic plaque calcification, such as osteopontin (OPN), osteoprotegerin (OPG) and the receptor activator of nuclear factor kappa-B ligand (RANKL) in a cohort of AIS patients (n=90) during 90-day follow up.Materials and methodsRadiological and clinical examinations as well as blood sampling were performed at admission and at day 1, 7 and 90 from the event. Validated scores (such as modified Rankin Score [mRS] and the National Institutes of Health Stroke Scale [NIHSS]) were used to assess post-stroke outcome. Serum levels of OPN, OPG and RANKL were measured by colorimetric enzyme-linked immunosorbent assay (ELISA).ResultsWhen compared to the admission, OPN serum levels increased at day 7. Serum OPN levels at this time point were positively correlated with both ischemic lesion volume and NIHSS at day 7 and 90. A cut-off of 30.53 ng/mL was identified for serum OPN by receiver operator curve (ROC) analysis. Adjusted logistic regression showed that serum OPN levels at day 7 predicted worse mRS at day 90 (OR 4.13 [95% CI 1.64-10.36]; p=0.002) and NIHSS (1.49 [95% CI 1.16-1.99]; p=0.007), independently of age, gender, hypertension and thrombolysis.Conclusion
Serum levels of OPN, but not OPG and RANKL peaked at day 7 after AIS and predicted worse neurological scores. Therefore, OPN might have a pathophysiological and clinical relevance after AIS.This article is protected by copyright. All rights reserved.
European Journal of Clinical Investigation 04/2015; 45(6). DOI:10.1111/eci.12446 · 2.73 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Paradoxically, morbid obesity was suggested to protect from cardiovascular co-morbidities as compared to overweight/obese patients. We hypothesise that this paradox could be inferred to modulation of the "endocannabinoid" system on systemic and subcutaneous adipose tissue (SAT) inflammation. We designed a translational project including clinical and in vitro studies at Geneva University Hospital. Morbid obese subjects (n=11) were submitted to gastric bypass surgery (GBS) and followed up for one year (post-GBS). Insulin resistance and circulating and SAT levels of endocannabinoids, adipocytokines and CC chemokines were assessed pre- and post-GBS and compared to a control group of normal and overweight subjects (CTL) (n=20). In vitro cultures with 3T3-L1 adipocytes were used to validate findings from clinical results. Morbid obese subjects had baseline lower insulin sensitivity and higher hs-CRP, leptin, CCL5 and anandamide (AEA) levels as compared to CTL. GBS induced a massive weight and fat mass loss, improved insulin sensitivity and lipid profile, decreased C-reactive protein, leptin, and CCL2 levels. In SAT, increased expression of resistin, CCL2, CCL5 and tumour necrosis factor and reduced MGLL were shown in morbid obese patients pre-GBS when compared to CTL. GBS increased all endocannabinoids and reduced adipocytokines and CC chemokines. In morbid obese SAT, inverse correlations independent of body mass index were shown between palmitoylethanolamide (PEA) and N-oleoylethanolamide (OEA) levels and inflammatory molecules. In vitro, OEA inhibited CCL2 secretion from adipocytes via ERK1/2 activation. In conclusion, GBS was associated with relevant clinical, metabolic and inflammatory improvements, increasing endocannabinoid levels in SAT. OEA directly reduced CCL2 secretion via ERK1/2 activation in adipocytes.
Thrombosis and Haemostasis 11/2014; 113(3). DOI:10.1160/TH14-06-0506 · 4.98 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: AIMS: Several intracellular mediators have been implicated as new therapeutic targets against myocardial ischaemia and reperfusion injury. However, clinically effective salvage pathways remain undiscovered. Here, we focused on the potential role of the adaptor protein p66(Shc) as a regulator of myocardial injury in a mouse model of cardiac ischaemia and reperfusion.
METHODS AND RESULTS: Adult male p66(Shc) deficient (p66(Shc) (-/-)) and C57Bl/6 wild-type (WT) mice were exposed to 30, 45, or 60 min of ischaemia and reperfusion (5, 15 min, or 24 h). Infarct size, systemic and intracardiac inflammation and oxidants, as well as cytosolic and mitochondrial apoptotic pathways were investigated. Following 30, but not 45 or 60 min of ischaemia, genetic p66(Shc) deficiency was associated with larger infarcts. In WT mice, in vivo p66(Shc) knock down by siRNA with transient protein deficiency confirmed these findings. P66(Shc) inhibition was not associated with any modification in post-infarction inflammation, oxidative burst nor cardiac vessel density or structure. However, in p66(Shc) (-/-) mice activation of the protective and anti-apoptotic Reperfusion Injury Salvage Kinases and Survivor Activating Factor Enhancement pathways were blunted and mitochondrial swelling and cellular apoptosis via the caspase-3 pathway increased compared with WT.
CONCLUSIONS: Genetic deletion of p66(Shc) increased susceptibility to myocardial injury in response to short-term ischaemia and reperfusion in mice. Still, additional studies are needed for assessing the role of this pathway in acute coronary syndrome patients.
European Heart Journal 10/2014; 36(8). DOI:10.1093/eurheartj/ehu400 · 15.20 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background
Acute pancreatitis is characterized by inflammatory processes affecting not only the pancreas, but also the lung. Here, we investigated timing of leukocyte infiltration and chemokine expression within lung and pancreas during pancreatitis and whether treatments selectively inhibiting chemokines (using Evasins) could improve organ injury.Material and methodsC57Bl/6 mice were submitted in vivo to 10-hourly intraperitoneal injections of cerulein and followed for up to 168 hours. Five minutes after the first cerulein injection, a single intraperitoneal injection of 10 μg Evasin-3, 1 μg Evasin-4 or an equal volume of vehicle (PBS) was performed. Leukocytes, reactive oxygen species (ROS), necrosis and chemokine/cytokine mRNA expression were assessed in different organs by immunohistology and Real time RT-PCR, respectively.ResultsIn the lung, neutrophil and macrophage infiltration peaked at 12 hours and was accompanied by increased CXCL2 mRNA expression. CCL2, CXCL1 and TNF-alpha significantly increased after 24 hours as compared to baseline. No increase in CCL3 and CCL5 was observed. In the pancreas, neutrophil infiltration peaked at 6 hours, while macrophages increased only after 72 hours. Treatment with Evasin-3 decreased neutrophil infiltration, ROS production and apoptosis in the lung and reduced neutrophils, macrophages apoptosis and necrosis in the pancreas. Evasin-4 only reduced macrophage content in the lung and did not provide any benefit at the pancreas level.Conclusion
Chemokine production and leukocyte infiltration are timely regulated in lung and pancreas during pancreatitis. CXC chemokine inhibition with Evasin-3 improved neutrophil inflammation and injury, potentially interfering with damages in acute pancreatitis and related pulmonary complications.This article is protected by copyright. All rights reserved.
European Journal of Clinical Investigation 08/2014; 44(10). DOI:10.1111/eci.12327 · 2.73 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Pharmacological treatments targeting CXC chemokines and the associated neutrophil activation and recruitment into atherosclerotic plaques hold promise for treating cardiovascular disorders. Therefore, we investigated whether FK866, a nicotinamide phosphoribosyltransferase (NAMPT) inhibitor with anti-inflammatory properties that we recently found to reduce neutrophil recruitment into the ischaemic myocardium, would exert beneficial effects in a mouse atherosclerosis model. Atherosclerotic plaque formation was induced by carotid cast implantation in ApoE-/- mice that were fed with a Western-type diet. FK866 or vehicle were administrated intraperitoneally from week 8 until week 11 of the diet. Treatment with FK866 reduced neutrophil infiltration and MMP-9 content and increased collagen levels in atherosclerotic plaques compared to vehicle. No effect on other histological parameters, including intraplaque lipids or macrophages, was observed. These findings were associated with a reduction in both systemic and intraplaque CXCL1 levels in FK866-treated mice. In vitro, FK866 did not affect MMP-9 release by neutrophils, but it strongly reduced CXCL1 production by endothelial cells which, in the in vivo model, were identified as a main CXCL1 source at the plaque level. CXCL1 synthesis inhibition by FK866 appears to reflect interference with nuclear factor-κB signalling as shown by reduced p65 nuclear levels in endothelial cells pre-treated with FK866. In conclusion, pharmacological inhibition of NAMPT activity mitigates inflammation in atherosclerotic plaques by reducing CXCL1-mediated activities on neutrophils. These results support further assessments of NAMPT inhibitors for the potential prevention of plaque vulnerability.
Thrombosis and Haemostasis 11/2013; 111(2). DOI:10.1160/TH13-07-0531 · 4.98 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Myocardial reperfusion injury is mediated by several processes including increase of reactive oxygen species (ROS). The aim of the study is to identify potential sources of ROS contributing to myocardial ischemia-reperfusion injury. For this purpose, we investigated myocardial ischemia/reperfusion pathology in mice deficient in various NADPH oxidase isoforms (Nox1, Nox2, Nox4, as well as Nox1/2 double knockout). Following 30minutes of ischemia and 24hours reperfusion, a significant decrease in the size of myocardial infarct was observed in Nox1-, Nox2- and Nox1/Nox2-, but not in Nox4-deficient mice. However, no protection was observed in a model of chronic ischemia, suggesting that NOX1 and NOX2-mediated oxidative damage occurs during reperfusion. Cardioprotective effect of Nox1 and Nox2 deficiencies was associated with decrease of neutrophil invasion, but, on the other hand an improved reperfusion injury was also observed in isolated perfused hearts (Langendorff model) suggesting that inflammatory cells were not the major source of oxidative damage. A decrease in global post-reperfusion oxidative stress was clearly detected in Nox2-, but not in Nox1-deficient hearts. Analysis of key signalling pathways during reperfusion suggest distinct cardioprotective patterns: increased phosphorylation was seen for Akt and Erk in Nox1-deficient mice and for Stat3 and Erk in Nox2-deficient mice. Consequently, NOX1 and NOX2 represent interesting drug targets for controlling reperfusion damage associated with revascularization in coronary disease.
Journal of Molecular and Cellular Cardiology 09/2013; 66. DOI:10.1016/j.yjmcc.2013.09.007 · 4.66 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Chemokines trigger leukocyte trafficking and are implicated in cardiovascular disease pathophysiology. Chemokine-binding proteins, called "Evasins" have been shown to inhibit both CC and CXC chemokine-mediated bioactivities. Here, we investigated whether treatment with Evasin-3 (CXC chemokine inhibitor) and Evasin-4 (CC chemokine inhibitor) could influence post-infarction myocardial injury and remodelling. C57Bl/6 mice were submitted in vivo to left coronary artery permanent ligature and followed up for different times (up to 21 days). After coronary occlusion, three intraperitoneal injections of 10 μg Evasin-3, 1 μg Evasin-4 or equal volume of vehicle (PBS) were performed at 5 minutes, 24 hours (h) and 48 h after ischaemia onset. Both anti-chemokine treatments were associated with the beneficial reduction in infarct size as compared to controls. This effect was accompanied by a decrease in post-infarction myocardial leukocyte infiltration, reactive oxygen species release, and circulating levels of CXCL1 and CCL2. Treatment with Evasin-4 induced a more potent effect, abrogating the inflammation already at one day after ischaemia onset. At days 1 and 21 after ischaemia onset, both anti-chemokine treatments failed to significantly improve cardiac function, remodelling and scar formation. At 21-day follow-up, mouse survival was exclusively improved by Evasin-4 treatment when compared to control vehicle. In conclusion, we showed that the selective inhibition of CC chemokines (i.e. CCL5) with Evasin-4 reduced cardiac injury/inflammation and improved survival. Despite the inhibition of CXC chemokine bioactivities, Evasin-3 did not affect mouse survival. Therefore, early inhibition of CC chemokines might represent a promising therapeutic approach to reduce the development of post-infarction heart failure in mice.
Thrombosis and Haemostasis 08/2013; 110(4). DOI:10.1160/TH13-04-0297 · 4.98 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Percutaneous transluminal angioplasty is frequently used in patients with severe arterial narrowing due to atherosclerosis. However, it induces severe arterial injury and an inflammatory response leading to restenosis. Here, we studied a potential activation of the endocannabinoid system and the effect of fatty acid amide hydrolase (FAAH) deficiency, the major enzyme responsible for endocannabinoid anandamide degradation, in arterial injury. We performed carotid balloon injury in atherosclerosis-prone apolipoprotein E knockout (ApoE-/-) and ApoE-/-FAAH-/- mice. Anandamide levels were systemically elevated in ApoE-/- mice after balloon injury. ApoE-/-FAAH-/- mice had significantly higher baseline anandamide levels and enhanced neointima formation compared to ApoE-/- controls. The latter effect was inhibited by treatment with CB1 antagonist AM281. Similarly, ApoE-/- mice treated with AM281 had reduced neointimal areas, reduced lesional vascular smooth muscle cell (SMC) content and proliferating cell counts. The lesional macrophage content was unchanged. In vitro proliferation rates were significantly reduced in CB1-/- SMCs or when treating ApoE-/- or ApoE-/-FAAH-/- SMCs with AM281. Macrophage in vitro adhesion and migration was marginally affected by CB1 deficiency. Reendothelialization was not inhibited by treatment with AM281. In conclusion, endogenous CB1 activation contributes to vascular SMC proliferation and neointima formation in response to arterial injury.
The Journal of Lipid Research 03/2013; 54(5). DOI:10.1194/jlr.M035147 · 4.42 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Neutrophilic inflammation might have a pathophysiological role in both carotid plaque rupture and ischemic stroke injury. Here, we investigated the potential benefits of the CXC chemokine-binding protein Evasin-3, which potently inhibits chemokine bioactivity and related neutrophilic inflammation in two mouse models of carotid atherosclerosis and ischemic stroke, respectively. In the first model, the chronic treatment with Evasin-3 as compared with Vehicle (phosphate-buffered saline (PBS)) was investigated in apolipoprotein E-deficient mice implanted of a 'cast' carotid device. In the second model, acute Evasin-3 treatment (5 minutes after cerebral ischemia onset) was assessed in mice subjected to transient left middle cerebral artery occlusion. Although CXCL1 and CXCL2 were upregulated in both atherosclerotic plaques and infarcted brain, only CXCL1 was detectable in serum. In carotid atherosclerosis, treatment with Evasin-3 was associated with reduction in intraplaque neutrophil and matrix metalloproteinase-9 content and weak increase in collagen as compared with Vehicle. In ischemic stroke, treatment with Evasin-3 was associated with reduction in ischemic brain neutrophil infiltration and protective oxidants. No other effects in clinical and histological outcomes were observed. We concluded that Evasin-3 treatment was associated with reduction in neutrophilic inflammation in both mouse models. However, Evasin-3 administration after cerebral ischemia onset failed to improve poststroke outcomes.Journal of Cerebral Blood Flow & Metabolism advance online publication, 19 December 2012; doi:10.1038/jcbfm.2012.198.
Journal of cerebral blood flow and metabolism: official journal of the International Society of Cerebral Blood Flow and Metabolism 12/2012; 33(4). DOI:10.1038/jcbfm.2012.198 · 5.41 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Objective:
Endocannabinoid levels are elevated in human and mouse atherosclerosis, but their causal role is not well understood. Therefore, we studied the involvement of fatty acid amide hydrolase (FAAH) deficiency, the major enzyme responsible for endocannabinoid anandamide degradation, in atherosclerotic plaque vulnerability.
Methods and results:
We assessed atherosclerosis in apolipoprotein E-deficient (ApoE(-/-)) and ApoE(-/-)FAAH(-/-) mice. Before and after 5, 10, and 15 weeks on high-cholesterol diet, we analyzed weight, serum cholesterol, and endocannabinoid levels, and atherosclerotic lesions in thoracoabdominal aortas and aortic sinuses. Serum levels of FAAH substrates anandamide, palmitoylethanolamide (PEA), and oleoylethanolamide (OEA) were 1.4- to 2-fold higher in case of FAAH deficiency. ApoE(-/-)FAAH(-/-) mice had smaller plaques with significantly lower content of smooth muscle cells, increased matrix metalloproteinase-9 expression, and neutrophil content. Circulating and bone marrow neutrophil counts were comparable between both genotypes, whereas CXC ligand1 levels were locally elevated in aortas of FAAH-deficient mice. We observed enhanced recruitment of neutrophils, but not monocytes, to large arteries of ApoE(-/-) mice treated with FAAH inhibitor URB597. Spleens of ApoE(-/-)FAAH(-/-) mice had reduced CD4+FoxP3+regulatory T-cell content, and in vitro stimulation of splenocytes revealed significantly elevated interferon-γ and tumor necrosis factor-α production in case of FAAH deficiency.
Increased anandamide and related FAAH substrate levels are associated with the development of smaller atherosclerotic plaques with high neutrophil content, accompanied by an increased proinflammatory immune response.
[Show abstract][Hide abstract] ABSTRACT: Cannabinoid receptor CB(2) activation inhibits inflammatory proliferation and migration of vascular smooth muscle cells in vitro. The potential in vivo relevance of these findings is unclear. We performed carotid balloon distension injury in hypercholesterolemic apolipoprotein E knockout (ApoE(-/-)) mice receiving daily intraperitoneal injection of the CB(2) agonist JWH133 (5 mg/kg) or vehicle, with the first injection given 30 min before injury. Alternatively, we subjected CB(2)(-/-) and wild-type (WT) mice to balloon injury. We determined CB(2) mRNA and protein expression in dilated arteries of ApoE(-/-) mice. Neointima formation was assessed histologically. We used bone marrow-derived murine CB(2)(-/-) and WT macrophages to study adhesion to plastic, fibronectin, or collagen, and migration was assayed by modified Boyden chamber. Aortic smooth muscle cells were isolated to determine in vitro proliferation rates. We found increased vascular CB(2) expression in ApoE(-/-) mice in response to balloon injury. Seven to twenty-one days after dilatation, injured vessels of JWH133-treated mice had less intimal nuclei numbers as well as intimal and medial areas, associated with less staining for proliferating cells, smooth muscle cells, and macrophages. Complete endothelial repair was observed after 14 days in both JWH133- and vehicle-treated mice. CB(2) deficiency resulted in increased intima formation compared with WT, whereas JWH133 did not affect intimal formation in CB(2)(-/-) mice. Apoptosis rates assessed by in situ terminal deoxynucleotidyl transferase dUTP-mediated nick-end labeling staining 1 h postballooning were significantly higher in the CB(2) knockouts. In vitro, bone marrow-derived CB(2)(-/-) macrophages showed enhanced adherence and migration compared with WT cells and elevated mRNA levels of adhesion molecules, chemokine receptors CCR1 and 5, and chemokine CCL2. Proliferation rates were significantly increased in CB(2)(-/-) smooth muscle cells compared with WT. In conclusion, pharmacological activation or genetic deletion of CB(2) receptors modulate neointima formation via protective effects in macrophages and smooth muscle cells.
[Show abstract][Hide abstract] ABSTRACT: The activation of cannabinoid receptor type 2 (CB(2))-mediated pathways might represent a promising anti-atherosclerotic treatment. Here, we investigated the expression of the endocannabinoid system in human carotid plaques and the impact of CB(2) pharmacological activation on markers of plaque vulnerability in vivo and in vitro.
The study was conducted using all available residual human carotid tissues (upstream and downstream the blood flow) from our cohort of patients symptomatic (n = 13) or asymptomatic (n = 27) for ischaemic stroke. Intraplaque levels of 2-arachidonoylglycerol, anandamide N-arachidonoylethanolamine, N-palmitoylethanolamine, N-oleoylethanolamine, and their degrading enzymes (fatty acid amide hydrolase and monoacylglycerol lipase) were not different in human plaque portions. In the majority of human samples, CB(1) (both mRNA and protein levels) was undetectable. In downstream symptomatic plaques, CB(2) protein expression was reduced when compared with asymptomatic patients. In these portions, CB(2) levels were inversely correlated (r = -0.4008, P = 0.0170) with matrix metalloprotease (MMP)-9 content and positively (r = 0.3997, P = 0.0174) with collagen. In mouse plaques, CB(2) co-localized with neutrophils and MMP-9. Treatment with the selective CB(2) agonist JWH-133 was associated with the reduction in MMP-9 content in aortic root and carotid plaques. In vitro, pre-incubation with JWH-133 reduced tumour necrosis factor (TNF)-α-mediated release of MMP-9. This effect was associated with the reduction in TNF-α-induced ERK1/2 phosphorylation in human neutrophils.
Cannabinoid receptor type 2 receptor is down-regulated in unstable human carotid plaques. Since CB(2) activation prevents neutrophil release of MMP-9 in vivo and in vitro, this treatment strategy might selectively reduce carotid vulnerability in humans.
European Heart Journal 11/2011; 33(7):846-56. DOI:10.1093/eurheartj/ehr449 · 15.20 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The highly prevalent obstructive sleep apnea syndrome (OSA) with its main component intermittent hypoxia (IH) is a risk factor for cardiovascular mortality. The poor knowledge of its pathophysiology has limited the development of specific treatments, whereas the gold standard treatment, continuous positive airway pressure, may not fully reverse the chronic consequences of OSA and has limited acceptance in some patients.
To examine the contribution of IH-induced inflammation to the cardiovascular complications of OSA. Methods: We investigated systemic and vascular inflammatory changes in C57BL6 mice exposed to IH (21-5% Fi(O(2)), 60-s cycle) or normoxia 8 hours per day up to 14 days. Vascular alterations were reassessed in mice treated with a blocking antibody of regulated upon activation, normal T-cell expressed and secreted (RANTES)/CC chemokine ligand 5 (CCL5) signaling pathway, or with the IgG isotype control throughout the IH exposure.
IH induced systemic inflammation combining increased splenic lymphocyte proliferation and chemokine expression, with early and predominant RANTES/CCL5 alterations, and enhanced splenocyte migration toward RANTES/CCL5. IH also induced structural and inflammatory vascular alterations. Leukocyte-endothelium adhesive interactions were increased, attested by leukocyte rolling and intercellular adhesion molecule-1 expression in mesenteric vessels. Aortas had increased intima-media thickness with elastic fiber alterations, mucoid depositions, nuclear factor-κB-p50 and intercellular adhesion molecule-1 overexpression, hypertrophy of smooth-muscle cells overexpressing RANTES/CCL5, and adventitial-periadventitial T-lymphocyte infiltration. RANTES/CCL5 neutralization prevented both intima-media thickening and inflammatory alterations, independently of the IH-associated proatherogenic dyslipidemia.
Inflammation is a determinant mechanism for IH-induced preatherosclerotic remodeling involving RANTES/CCL5, a key chemokine in atherogenesis. Characterization of the inflammatory response could allow identifying at-risk patients for complications, and its pharmacologic manipulation may represent a potential complementary treatment of sleep apnea consequences.
American Journal of Respiratory and Critical Care Medicine 06/2011; 184(6):724-31. DOI:10.1164/rccm.201012-2033OC · 13.00 Impact Factor