[Show abstract][Hide abstract] ABSTRACT: Background:
Percutaneous coronary intervention (PCI) is an effective treatment for patients with ischemic heart disease. In particular, restenosis is suppressed after drug-eluting stent (DES) implantation. However, several problems remain. Previously, we reported neointimal proliferation after DES implantation, which was associated with insulin resistance (IR). The aim of the present study was to clarify whether IR is associated with mortality and major adverse cardiac and cerebrovascular events (MACCE) after 1st-generation DES implantation.Methods and Results:We researched the clinical records of 109 patients who had undergone elective PCI and DES implantation between May 2007 and December 2010. We segregated these patients according to the value of the homeostasis model assessment of IR (HOMA-IR) into Group P (n=63; HOMA-IR ≥2.5, positive) and Group N (n=46; HOMA-IR <2.5, negative), and examined the relationship between HOMA-IR and MACCE. The observation period was 7.4±1.6 years. There were no differences between the 2 groups in the occurrence of all-cause death, cardiac death, restenosis, myocardial infarction, stroke, heart failure, or stent thrombosis. However, the late catch-up phenomenon was significantly more common in Group P than in Group N (12.7% vs. 2.2% P=0.048).
IR is a useful predictor of the late catch-up phenomenon after DES implantation, and improvement of IR may help to prevent the phenomenon.
Full-text · Article · Jan 2016 · Circulation Journal
[Show abstract][Hide abstract] ABSTRACT: It has been suggested that n-3 polyunsaturated fatty acids, such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), protect against cardiovascular diseases, and EPA/arachidonic acid (AA) and DHA/AA ratios in serum are potential risk markers for coronary artery disease (CAD). The purpose of this study was to clarify the clinical significance of the difference in the EPA/AA ratio and the DHA/AA ratio in patients with CAD. In 369 patients with confirmed or suspected CAD who underwent diagnostic coronary angiography, we measured serum levels of EPA, DHA and AA and calculated the EPA/AA and DHA/AA ratios. The EPA/AA ratio was significantly lower in patients with acute coronary syndrome (ACS) than in patients with chronic CAD or chest pain syndrome (0.27±0.19 vs. 0.44±0.20, respectively; P<0.01), whereas the DHA/AA ratio was similar in the two groups (0.78±0.27 vs. 0.79±0.37). Multiple logistic regression analyses using various biomarkers related to coronary risk discriminated ACS from other disease entities and demonstrated that the EPA/AA ratio (odds ratio: 0.0012, 95% confidence interval: 0.00-0.16, P<0.01) but not the DHA/AA ratio (odds ratio: 1.05, 95% confidence interval: 0.98-1.12) was a significant independent predictive factor. Our findings suggest that the EPA/AA ratio might be more closely associated with the pathophysiology of CAD, especially with that of ACS, than the DHA/AA ratio. Our findings suggest that interventions with EPA agents or supplemental EPA intake, compared with DHA agents or supplemental DHA, may confer greater benefit for plaque stabilization to prevent the onset of ACS in patients with CAD.Hypertension Research advance online publication, 7 January 2016; doi:10.1038/hr.2015.143.
No preview · Article · Jan 2016 · Hypertension Research
[Show abstract][Hide abstract] ABSTRACT: Experimental ischemia-reperfusion models have shown that 3-hydroxy-3methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, statins, have cardioprotective effects. SAMIT (Statin Acute Myocardial Infarction Trial) is a multicenter prospective open randomized trial, designed to evaluate the effects of statin treatment from the earliest stage on cardioprotection in patients with acute myocardial infarction (AMI). Patients were randomly assigned to receive atorvastatin (initial dose of 40 mg at admission followed by the maintenance dose of 10 mg/day for 30 days) or not (control), and then immediately underwent percutaneous coronary intervention (PCI) for the culprit lesion. The primary endpoints were infarct size and left ventricular function. The secondary endpoints were major adverse cardiac and cerebrovascular events (MACCE) and various biomarkers. There were no significant differences in baseline characteristics between 2 groups of the statin treatment group and the control group. The left ventricular ejection fraction increased at 6 months after the onset of AMI, compared with the baseline level in the atorvastatin group (P < 0.05), while it did not change in the control group. Although there were no significant differences in the MACCE, the changes in the levels of angiopoietin-like protein 2 (ANGPTL2) (P < 0.05), and glyceraldehyde-derived advanced glycation end-products, (TAGE) (P < 0.01) were suppressed at 2 weeks in the atorvastatin group, compared with the control group. Statin therapy started early after the onset reduced the levels of ANGPTL2 and TAGE, and thus, might have cardioprotective effects in patients with AMI.
No preview · Article · Dec 2015 · Heart and Vessels
[Show abstract][Hide abstract] ABSTRACT: Although exercise oscillatory ventilation has emerged as a potent independent risk factor for adverse prognosis in heart failure, it is not well known whether cardiac rehabilitation can improve oscillatory ventilation. In this study, we investigated the magnitude of oscillations in ventilation before and after cardiac rehabilitation in chronic heart failure patients with exercise oscillatory ventilation. Cardiac rehabilitation (5-month program) was performed in 26 patients with chronic heart failure who showed an oscillatory ventilation pattern during cardiopulmonary exercise testing (CPX). After the 5-month rehabilitation program was completed, the patients again underwent CPX. To determine the magnitude of oscillations in ventilation, the amplitude and cycle length of the oscillations were calculated and compared with several other parameters, including biomarkers that have established prognostic value in heart failure. At baseline before cardiac rehabilitation, both oscillation amplitude (R = 0.625, P < 0.01) and cycle length (R = 0.469, P < 0.05) were positively correlated with the slope of minute ventilation vs. carbon dioxide production. Plasma BNP levels were positively correlated with amplitude (R = 0.615, P < 0.01) but not cycle length (R = 0.371). Cardiac rehabilitation decreased oscillation amplitude (P < 0.01) but failed to change cycle length. The change in amplitude was positively correlated with the change in BNP levels (R = 0.760, P < 0.01). Multiple regression analysis showed that only the change in amplitude was an independent predictor of the change in BNP levels (R = 0.717, P < 0.01). A 5-month cardiac rehabilitation program improves exercise oscillatory ventilation in chronic heart failure patients by reducing the oscillation amplitude. This effect is associated with a reduction of plasma BNP levels, potentially contributing to an improvement of heart failure.
No preview · Article · Dec 2015 · Heart and Vessels
[Show abstract][Hide abstract] ABSTRACT: Background:
The impact of obstructive sleep apnoea on heart failure with preserved ejection fraction is unknown.
Fifty-eight patients who had heart failure with a left ventricular ejection fraction; ≥50% underwent a sleep study. Brain natriuretic peptide (BNP) levels were determined at enrolment and at one, six, 12 and 36 months after enrolment.
Obstructive sleep apnoea was found in 39 patients (67%), and they were all subsequently treated with continuous positive airway pressure. Echocardiography at admission showed that E/E' tended to be higher in the 39 patients with, than in the 19 patients without, obstructive sleep apnoea (15.0±3.6 vs 12.1±1.9, respectively, P=0.05). The median BNP levels at enrolment were similar in patients with and without obstructive sleep apnoea [median (interquartile range): 444 (233-752) vs 316 (218-703) pg/ml]. Although BNP levels decreased over time in both groups, the reduction was less pronounced in patients with obstructive sleep apnoea (P<0.05). Consequently, BNP levels were higher in patients with sleep apnoea at six months, [221 (137-324) vs 76 (38-96) pg/ml, P<0.05], 12 months [123 (98-197) vs 52 (38-76) pg/ml, P<0.05] and 36 months [115 (64-174) vs 56 (25-74) pg/ml, P<0.05].
Obstructive sleep apnoea, even when treated appropriately, may worsen long-term cardiac function and outcomes in patients who have heart failure with preserved ejection fraction.
No preview · Article · Oct 2015 · Heart, Lung and Circulation
[Show abstract][Hide abstract] ABSTRACT: Overall stent performance should be characterized by geometric luminal gain acquisition, neointimal coverage of the stent struts, and stabilization of the underlying inflammatory neoatheroma. The aim of this study was to compare the performance of zotarolimus-eluting stent (ZES), everolimus-eluting stent (EES) and bare metal stent (BMS) using optical coherence tomography (OCT) and coronary angioscopy. For 36 stented coronary lesions (BMS, 12 lesions; ZES, 11 lesions; EES, 13 lesions) in 27 patients, we calculated neointimal area and uncovered stent strut rate based on OCT findings at 10 months after stent placement. The grades of neointimal coverage and yellow color, both of which were classified from 0 to 3, were also assessed by coronary angioscopy. The plaque area of the ZES lesions was larger than that of the EES lesions (P < 0.05) but smaller than that of the BMS lesions (P < 0.05). The OCT-based uncovered rate of the ZES lesions was less than that of the EES lesions (P < 0.01), but similar to that of the BMS lesions. The stent coverage grade by angioscopy was higher in the ZES lesions than in the EES lesions (P < 0.05), but similar to the BMS lesions. The yellow grade was less in the ZES lesions than in the EES lesions (P < 0.01), but similar to the BMS lesions. ZES might be better than BMS in terms of neointimal thickening, and better than EES in terms of neointimal coverage as well as prevention of neoatheroma formation. ZES may have superior performance compared with EES.
No preview · Article · Aug 2015 · Heart and Vessels
[Show abstract][Hide abstract] ABSTRACT: A 70-year-old man underwent stent implantation for right coronary artery (RCA) lesions with a bare metal stent (BMS) and two sirolimus-eluting stents (SES). However, as both the BMS and SES stented sites developed restenosis after 13 months, he underwent target lesion revascularization using directional coronary atherectomy (DCA). On histopathology, the restenosis lesion at the SES-deployed site showed greater inflammation and less re-endothelialization than that at the BMS-deployed site. Three months later, the SES-deployed site developed a second restenosis, in which paclitaxel-eluting stents (PES) were implanted (PES-in-SES), while the BMS-deployed site was restenosis free. Five years later, restenosis was absent in these RCA lesions. However, by optical coherence tomography and/or coronary angioscopy, the PES-in-SES site in the RCA showed poor neointimal coverage over the stent struts and yellowish neointima, suggesting lipid-rich neoatheroma formation, whereas at the BMS site appropriate white neointima formation was observed. Drug-eluting stents still have problems of persistent inflammation, inappropriate neointima formation, and neoatherosclerosis. Although we are now in the era of second generation DESs in which better stent performance would be promising, we should remember that we are obliged to continue to follow-up all patients in whom first generation DESs such as SES or PES have been placed.
No preview · Article · May 2015 · Heart and Vessels
[Show abstract][Hide abstract] ABSTRACT: Expression of the gene encoding the S100 calcium-modulated protein family member MRP-14 (also known as S100A9) is elevated in platelets from patients presenting with acute myocardial infarction (MI) compared with those from patients with stable coronary artery disease; however, a causal role for MRP-14 in acute coronary syndromes has not been established. Here, using multiple models of vascular injury, we found that time to arterial thrombotic occlusion was markedly prolonged in Mrp14-/- mice. We observed that MRP-14 and MRP-8/MRP-14 heterodimers (S100A8/A9) are expressed in and secreted by platelets from WT mice and that thrombus formation was reduced in whole blood from Mrp14-/- mice. Infusion of WT platelets, purified MRP-14, or purified MRP-8/MRP-14 heterodimers into Mrp14-/- mice decreased the time to carotid artery occlusion after injury, indicating that platelet-derived MRP-14 directly regulates thrombosis. In contrast, infusion of purified MRP-14 into mice deficient for both MRP-14 and CD36 failed to reduce carotid occlusion times, indicating that CD36 is required for MRP-14-dependent thrombosis. Our data identify a molecular pathway of thrombosis that involves platelet MRP-14 and CD36 and suggest that targeting MRP-14 has potential for treating atherothrombotic disorders, including MI and stroke.
No preview · Article · Apr 2014 · The Journal of clinical investigation
[Show abstract][Hide abstract] ABSTRACT: Purpose: In order to investigate the effect of pitavastatin therapy on chronic heart failure (CHF), we examined the relationship between pitavastatin therapy and plasma interleukin-8 (IL-8) levels in this substudy of the PEARL (the pitavastatin heart failure) study.
Methods: We analyzed 242 symptomatic CHF patients with left ventricular ejection fraction (LVEF) of <45% were randomly allocated to either receive pitavastatin (2mg/day) or not in addition to conventional therapy for heart failure during an median follow-up of 35.5 months. The primary outcome was a composite of cardiac death and hospitalization for worsening heart failure.
Results: Plasma levels of IL-8 at baseline were measured in control group (n=121) and pitavastatin group (n=121). The median value of plasma IL-8 was 8.29pg/ml. These enrolled patients were divided into two groups according to the IL-8 median value. Incidence of the primary outcome was significantly higher in patients with IL-8>8.29pg/ml compared to patients with IL-8≤8.29pg/ml (hazard ratio=2.98, 95% confidence interval (CI): 1.54-5.79; P=.0007). In patients with IL-8≤8.29pg/ml, incidence of the primary outcome was no difference between control group (n=7) and pitavastatin group (n=5). On the contrary, in patients with IL-8>8.29pg/ml, incidence of the primary outcome was significantly lower in pitavastatin group (n=13) compared to control group (n=19) (hazard ratio=0.494, 95% CI: 0.24-1.00; P=.047). Furthermore, all these patients were divided into two groups according to the LVEF based on the predefined subgroup analysis, which showed a strongly significant statistical interaction between the effect of pitavastatin and LVEF (P=0.004). In patients with <30% of LVEF (n=69), incidence of the primary outcome was no difference between patients with IL-8>8.29pg/ml and patients with IL-8≤8.29pg/ml. Interestingly, in patients with ≥30% of LVEF (n=173), incidence of the primary outcome were significantly higher in patients with IL-8>8.29pg/ml compared to patients with IL-8≤8.29pg/ml (hazard ratio=3.295, 95% (CI): 1.37-7.95; P=.0049). Regarding the combination of patients with ≥30% of LVEF (n=173) and IL-8>8.29pg/ml, pitavastain therapy significantly reduced the primary outcome compared to conventional therapy (hazard ratio=0.265, 95% (CI): 0.09-0.76; P=.0086).
Conclusions: These findings indicate that pitavastatin therapy provided the benefit to reduce the high IL-8 levels in patients with chronic heart failure (EF≥30%) but not chronic heart failure (EF<30%). Thus IL-8 may play a key role in dispelling the effect of pitavastatin on the heart failure.
Full-text · Article · Aug 2013 · European Heart Journal
[Show abstract][Hide abstract] ABSTRACT: Glucagon-like peptide 1 (GLP-1), one of the incretin hormones, has been reported to increase positive inotropic activity in cardiac myocytes and protect against myocardial injury. However, the effects upon endothelial cells and the mechanisms involved are not fully understood. We assessed the hypothesis that GLP-1 has protective effects against inflammation and oxidative stress on human endothelial cells.
The effects of the GLP-1 analog liraglutide upon TNF-α-induced injury of the human umbilical vein endothelial cells (HUVECs) were evaluated. First, ROS induced by TNF-α was measured by staining with CM-H(2)DCFDA. Intracellular ROS production of HUVECs was significantly decreased in a dose-dependent manner until 30 nM while liraglutide inhibited the induction of gp91(phox) and p22(phox), subunit of NADPH oxidase, by TNF-α. In addition, protein levels of SOD-2, catalase and GPx were significantly increased by liraglutide. Second, rapid translocation of PKC-α into the membrane following TNF-α was evident. Liraglutide significantly inhibited this very rapid TNF-α-induced translocation of PKC-α into membrane at 2.5 min. Third, liraglutide significantly inhibited NF-κB activation and upregulated I-κB family while phosphorylation of IKK-α/β, which is upstream of NF-κB signaling, was also downregulated after 15 min of TNF-α treatment. Finally, liraglutide inhibited apoptosis of HUVEC and expression of Pentraxin-3 induced by TNF-α.
Liraglutide exerts marked anti-oxidative and anti-inflammatory effects on endothelial cells with inhibition of PKC-α, NADPH oxidase, NF-κB signaling and upregulation of protective anti-oxidative enzymes.
[Show abstract][Hide abstract] ABSTRACT: After stent-related vascular injury, an inflammatory response triggers the mobilization of bone marrow-derived stem cells, including both endothelial and smooth muscle progenitors, leading to re-endothelialization as well as restenosis. It has been postulated that neutrophil-released matrix metalloproteinase-9 (MMP-9) induces stem cell mobilization.
To elucidate the mechanistic link between inflammation and stem cell mobilization after coronary stenting.
In 31 patients undergoing coronary stenting, we serially measured activated Mac-1 on the surface of neutrophils and active MMP-9 levels in the coronary sinus blood plasma, and the number of circulating CD34-positive cells in the peripheral blood.
After bare-metal stent implantation (n=21), significant increases in the numbers of CD34-positive cells (maximum on post-procedure day 7, P<0.001), activated Mac-1 (at 48 h, P<0.001), and active MMP-9 levels (at 24h, P<0.001) were observed. However, these changes were absent after sirolimus-eluting stent implantation (n=10). In overall patients, the numbers of CD34-positive cells on day 7 (R=0.58, P<0.01) and activated Mac-1 at 48 h (R=0.58, P<0.01) were both correlated with active MMP-9 levels at 24h. Stimulation of activated Mac-1 on the surface of isolated human neutrophils produced active MMP-9 release in vitro.
These results suggest that stent-induced activation of Mac-1 on the surface of neutrophils might trigger their MMP-9 release, possibly leading to the mobilization of bone marrow-derived stem cells. These reactions were substantially inhibited by sirolimus-eluting stents.
No preview · Article · Nov 2011 · International journal of cardiology
[Show abstract][Hide abstract] ABSTRACT: The cellular and molecular processes that control vascular injury responses after percutaneous coronary intervention involve a complex interplay among vascular cells and progenitor cells that control arterial remodeling, neointimal proliferation, and re-endothelialization. Drug-eluting stents (DES) improve the efficacy of percutaneous coronary intervention by modulating vascular inflammation and preventing neointimal proliferation and restenosis. Although positive effects of DES reduce inflammation and restenosis, negative effects delay re-endothelialization and impair endothelial function. Delayed re-endothelialization and impaired endothelial function are linked to stent thrombosis and adverse clinical outcomes after DES use. Compared with bare-metal stents, DES also differentially modulate mobilization, homing, and differentiation of vascular progenitor cells involved in re-endothelialization and neointimal proliferation. The effects of DES on vascular inflammation and repair directly impact clinical outcomes with these devices and dictate requirements for extended-duration dual antiplatelet therapy.
Full-text · Article · Oct 2011 · JACC. Cardiovascular Interventions
[Show abstract][Hide abstract] ABSTRACT: Telmisartan, an angiotensin II type 1 receptor blocker (ARB), acts as a partial agonist for peroxisome proliferator-activated receptor-γ, and thus improves abnormalities of glucose metabolism and hypertriglyceridaemia in addition to its documented blood pressure-lowering effects. Recently, it has been demonstrated that telmisartan also lowers the levels of total cholesterol and low-density lipoprotein (LDL) cholesterol levels. This study was designed to investigate the mechanism of cholesterol reduction.
We measured serum levels of cholestanol, a cholesterol absorption marker, and lathosterol, a cholesterol synthesis marker, in 20 patients with both hypercholesterolaemia and hypertension. Ten patients were treated with telmisartan and the remaining 10 with fluvastatin.
After 3 months of treatment, total and LDL cholesterol levels decreased in the telmisartan group (P<0.01 for both total and LDL cholesterol levels) and the fluvastatin group (P<0.001 for both total and LDL cholesterol levels). The change in cholestanol level after 3 months of treatment was positively correlated with the levels of total (R=0.72, P<0.05) and LDL cholesterol (R=0.81, P<0.01) in the telmisartan group. The change in lathosterol level was positively correlated with the levels of total (R=0.88, P=0.001) and LDL cholesterol (R=0.89, P=0.001) in the fluvastatin group.
Our results suggest that the cholesterol-lowering effect of telmisartan might be caused by inhibition of cholesterol absorption, whereas that of statins is by inhibition of cholesterol synthesis. If confirmed, co-treatment with the two agents may be useful for synergistically lowering cholesterol in hypertensive patients.
No preview · Article · Feb 2011 · Journal of Clinical Pharmacy and Therapeutics
[Show abstract][Hide abstract] ABSTRACT: After vascular injury such as stent implantation, it has been suggested that the inflammatory response triggers mobilization of bone marrow-derived stem cells including both endothelial and smooth muscle progenitor cells, leading to re-endothelialization as well as restenoisis.. It has been postulated that neutrophil-released matrix metalloproteinase-9 (MMP-9) induces stem cell mobilization. To elucidate the mechanistic linkage between inflammation and stem cell mobilization, we serially measured circulating CD34-positive mononuclear cells, binding of 8B2, an antibody recognizing activation dependent neoepitope of integrin Mac-1, on the surface of neutrophils and active matrix metalloproteinase (MMP)-9 levels in 30 patients undergoing coronary stenting. After implantation of bare-metal stents, significant increases in the number of CD34-positive cells (maximum at the day 7, P<0.001), 8B2 binding (at 48 h, P<0.001), and active MMP-9 level (at 24 h, P<0.001) were observed. However, these changes were absent after implantation of sirolimus-eluting stents. In all patients, MMP-9 level at 24 h was correlated with the number of CD34-positive cells at day 7 (R=0.38, P<0.05) as well as 8B2 binding at 48 h (R=0.42, P<0.01). In patients who were implanted bare-metal stents, multiple regression analysis showed that angiographic late lumen loss was independently predicted by the number of CD34-positive cells at day 7 (R=34, P<0.05), 8B2 binding at 48 h (R=0.38, P<0.01), and MMP-9 levels at 24 h (R=0.32, P<0.05). In human isolated neutrophils taken from 5 healthy volunteers, stimulation of Mac-1 neoepitope by 8B2 antibody induced activated MMP-9 peoduction more than isotype control (P<0.01). Vascular injury by stent implantation may locally produce MMP-9, possibly leading to mobilization of bone marrow-derived stem cells, and subsequently to restenosis. Activation of neutrophil Mac-1 may greatly contribute to MMP-9 production. Excessive inhibition of these reactions by drug-eluting stents raise novel issues of present drug-eluting stents such as re-endothelialization failure.
[Show abstract][Hide abstract] ABSTRACT: To investigate whether the presence of decay-accelerating factor (or CD55), an intrinsic complement regulator, protects against the development of vascular disease, given that complement activation can affect leukocytes and platelets.
Leukocyte-platelet complexes are critical for the initiation and progression of atherosclerosis and restenosis; however, the mechanism by which these processes promote vascular injury is incompletely defined. We performed femoral artery wire injury in Daf1(-/-) mice and their wild-type controls. Leukocyte accumulation, cellular proliferation, and neointimal thickening were enhanced in Daf1(-/-) mice versus wild-type mice. Deficiency of either the C3a or the C5a receptor, respectively, reversed the increased vascular inflammation, cellular proliferation, and neointimal formation in Daf1(-/-) mice.
Decay-accelerating factor control of C3a and C5a generation and prevention of the binding of these activation fragments to the C3a and C5a receptors are critical for the biological response to vascular injury. Targeting the C3a and C5a receptors may be useful for the prevention of neointimal hyperplasia.
Full-text · Article · Mar 2010 · Arteriosclerosis Thrombosis and Vascular Biology
[Show abstract][Hide abstract] ABSTRACT: Myeloid-related protein (MRP)-8 (S100A8) and MRP-14 (S100A9) are members of the S100 family of calcium-modulated proteins that regulate myeloid cell function and control inflammation, in part, through activation of Toll-like receptor-4 and the receptor for advanced glycation end products. A transcriptional profiling approach in patients with acute coronary syndromes identified MRP-14 as a novel predictor of myocardial infarction. Further studies demonstrated that elevated plasma levels of MRP-8/14 heterodimer predict increased risk of first and recurrent cardiovascular events. Beyond its serving as a risk marker, whether MRP-8/14 participates directly in vascular inflammation and disease remains unclear.
We evaluated vascular inflammation in wild-type and MRP-14-deficient (MRP-14(-/-)) mice that lack MRP-8/14 complexes with experimental arterial injury, vasculitis, or atherosclerosis. After femoral artery wire injury, MRP-14(-/-) mice had significant reductions in leukocyte accumulation, cellular proliferation, and neointimal formation compared with wild-type mice. In a cytokine-induced local Shwartzman-like reaction that produces thrombohemorrhagic vasculitis, MRP-14(-/-) mice had significant reductions in neutrophil accumulation, lesion severity, and hemorrhagic area. In response to high-fat feeding, mice doubly deficient in apolipoprotein E and MRP-8/14 complexes had attenuation in atherosclerotic lesion area and in macrophage accumulation in plaques compared with mice deficient in apolipoprotein E alone.
This study demonstrates that MRP-8/14 broadly regulates vascular inflammation and contributes to the biological response to vascular injury by promoting leukocyte recruitment.
[Show abstract][Hide abstract] ABSTRACT: Down-regulation of the forkhead transcription factor Foxp1 by integrin engagement controls monocyte differentiation in vitro. To determine whether Foxp1 plays a critical role in monocyte differentiation and macrophage functions in vivo, we generated transgenic mice (macFoxp1tg) overexpressing human FOXP1 in monocyte/macrophage lineage cells using the CD68 promoter. Circulating blood monocytes from macFoxp1tg mice have reduced expression of the receptor for macrophage colony-stimulating factor (c-Fms/M-CSFR), impaired migratory capacity, and diminished accumulation as splenic macrophages. Macrophage functions, including cytokine production, phagocytosis, and respiratory burst were globally impaired in macFoxp1tg compared with wild-type cells. Osteoclastogenesis and bone resorption activity were also attenuated in macFoxp1tg mice. In models of chemical and bacterial peritonitis, macFoxp1tg mice exhibited reduced macrophage accumulation, bacterial clearance, and survival. Enforced overexpression of c-Fms/M-CSFR reversed the cytokine production and phagocytosis defects in macFoxp1tg macrophages, indicating that repression of c-fms/M-CSFR is likely the dominant mechanism responsible for Foxp1 action in monocyte differentiation and macrophage function. Taken together, these observations identify down-regulation of Foxp1 as critical for monocyte differentiation and macrophage functions in vivo.
[Show abstract][Hide abstract] ABSTRACT: In allograft rejection, recipient leukocytes and alloantibodies first target donor endothelial cells. Although the leukocyte integrin Mac-1 (alpha(Mbeta2), CD11b/CD18) facilitates cell-cell interactions among leukocytes and interactions between leukocytes and endothelial cells or platelets, its role in allograft survival and vasculopathy is incompletely defined.
This study examined parenchymal rejection and graft arterial disease after total allomismatched cardiac transplantation (BALB/c donor heart and B6 recipients) in wild-type (WT) and Mac-1-deficient (Mac-1(-/-)) recipients. Recipient Mac-1 deficiency attenuated parenchymal rejection and significantly prolonged cardiac allograft survival from 8.3+/-1.3 days in WT recipient allografts (n=18) to 13.8+/-2.3 days in Mac-1(-/-) recipient allografts (n=6; P<0.0001). Accumulation of neutrophils and macrophages significantly decreased in Mac-1(-/-) compared with WT recipients. Adoptive transfer of WT but not Mac-1(-/-) macrophages to Mac-1(-/-) recipients exacerbated parenchymal rejection and reduced allograft survival; in contrast, adoptive transfer of WT neutrophils did not affect graft survival. Mac-1(-/-) macrophages expressed significantly lower levels of costimulatory molecules both in vivo and in vitro, and mixed lymphocyte reaction using alloantigen-primed Mac-1(-/-) macrophages resulted in significantly lower antigen-presenting function than for WT macrophages. Tumor necrosis factor-alpha production also fell in cultures with Mac-1(-/-) macrophages. Despite attenuation of acute rejection, recipient Mac-1-deficiency did not prevent late graft arterial disease.
These studies demonstrate critical participation of Mac-1 in alloresponses during cellular allograft rejection. These observations establish a molecular target for modulating recipient responses to prolong graft survival.
[Show abstract][Hide abstract] ABSTRACT: To assess the importance of the interaction between leukocyte integrin Mac-1 (a Mb 2) and platelet glycoprotein (GP) Ib-a for leukocyte recruitment after vascular injury and the effect of the neutralization of the Mac-1-GPIba interaction on cell proliferation and the neointimal hyperplasia triggered by the vascular injury.
A peptide called M2 or anti-M2 antibody was developed to block the Mac-1-GPIba interaction. This peptide was injected and compared to a control-peptide in C57B1/6J mice submitted to vascular injury of the femoral artery with a guide wire. One, five or 28 days after the vascular injury, the femoral arteries were removed for morphometric and immunohistochemical analyses.
The blocking of the Mac-1-GPIba interaction promoted a statistically significant reduction in the number of leukocytes in the neointimal layer on the first day after the vascular injury (control: 7.9+/-5.0% of the cell total versus anti-M2: 2.0+/-1.6%, p=0.021), as well as determined a statistically significant decrease in leukocyte accumulation in the neointimal layer on days 5 and 28 (control: 42.3+/-12.9% versus anti-M2: 24.6+/-10.8%, p=0.047 and control: 7.9+/-3.0% versus anti-M2: 3.3+/-1.3%, p=0.012; respectively). Cell proliferation in the neointimal layer of the vessel five days post-injury was reduced with the blocking of the Mac-1-GPIba interaction (control: 5.0+/-2.9% of the cell total versus anti-M2: 1.8+/-0.5%; p=0.043), along with a significant decrease in cell proliferation in the vessel neointimal layer 28 days post-injury (control: 3.8+/-1.7% versus anti-M2: 2.0+/-1.2%; p=0.047). The blocking of the Mac-1-GPIba interaction also determined a statistically significant decrease of the intimal thickening 28 days post-injury (control: 10,395+/-3,549 microm(2) versus anti-M2: 4,561+/-4,915 microm(2); p=0.012).
Leukocyte recruitment after a vascular injury depends on the Mac-1-GPIba interaction and the neutralization of this interaction inhibits cell proliferation and neointimal formation.
Full-text · Article · Feb 2008 · Arquivos brasileiros de cardiologia