Biomedical subjects

Robert Moumdjian

Publications and source records attributed to Robert Moumdjian.

16 recordsLinked to original sources

PubMed2006

The response to brain tumor-derived growth factors is altered in radioresistant human brain endothelial cells.

INTRODUCTION: Radioresistant brain tumor vasculature is thought to hamper the efficiency of adjuvant cancer therapies. However, little is known regarding the signalling pathways involved in the angiogenic response to brain tumor-derived growth factors in irradiated human brain microvascular endothelial cells (HBMEC). The goal of this study is to assess the effect of ionizing radiation (IR) on HBMEC survival, migration and tubulogenesis. METHODS: HBMEC were cultured and irradiated at sublethal single doses. Cell survival was assessed by nuclear cell counting and flow cytometry. HBMEC migration in response to brain tumor-derived growth factors (U-87 GF) and tubulogenesis were assayed using modified Boyden chambers and Matrigel, respectively. RESULTS: We observed that single administration of 3-10 Gy IR doses only reduced cell survival by 30%. Radioresistant HBMEC overexpressed RhoA, a small GTPase protein regulating cellular adhesion and migration, and Rho-kinase (ROK), a serine-threonine protein kinase and one of RhoA's major targets. HBMEC migration was induced by vascular endothelial growth factor (VEGF), but even more so in response to sphingo-sine-1-phosphate (S1P) and to U-87 GF. Following IR exposure, HBMEC basal migration increased more than two-fold, whereas the response to S1P and to U-87 GF was significantly diminished. Similarly, the inhibitor of ROK Y-27632 decreased HBMEC migration in response to S1P and U-87 GF. Overexpression of RhoA decreased tubulogenesis, an effect also observed in irradiated HBMEC. CONCLUSION: Our results suggest that radioresistant HBMEC migration response to tumor-secreted growth factors and tubulogenesis are altered following IR. The RhoA/ROK signalling pathway is involved in the IR-altered angiogenic functions and may represent a potential molecular target for enhancing the impact of radiotherapy on tumor-associated endothelial cells.

Apoptosis↗

PubMed2006

Combined low dose ionizing radiation and green tea-derived epigallocatechin-3-gallate treatment induces human brain endothelial cells death.

The microvasculature of brain tumors has been proposed as the primary target for ionizing radiation (IR)-induced apoptosis. However, the contribution of low dose IR-induced non-apoptotic cell death pathways has not been investigated. This study aimed to characterize the effect of IR on human brain microvascular endothelial cells (HBMEC) and to assess the combined effect of epigallocatechin-3-gallate (EGCg), a green tea-derived anti-angiogenic molecule. HBMEC were treated with EGCg, irradiated with a sublethal (< or =10 Gy) single dose. Cell survival was assessed 48 h later by nuclear cell counting and Trypan blue exclusion methods. Cell cycle distribution and DNA fragmentation were evaluated by flow cytometry (FC), cell death was assessed by fluorimetric caspase-3 activity, FC and immunoblotting for pro-apoptotic proteins. While low IR doses alone reduced cell survival by 30%, IR treatment was found more effective in EGCg pretreated-cells reaching 70% cell death. Analysis of cell cycle revealed that IR-induced cell accumulation in G2-phase. Expression of cyclin-dependent kinase inhibitors p21(CIP/Waf1) and p27(Kip) were increased by EGCg and IR. Although random DNA fragmentation increased by approximately 40% following combined EGCg/IR treatments, the synergistic reduction of cell survival was not related to increased pro-apoptotic caspase-3, caspase-9 and cytochrome C proteins. Cell necrosis increased 5-fold following combined EGCg/IR treatments while no changes in early or late apoptosis were observed. Our results suggest that the synergistic effects of combined EGCg/IR treatments may be related to necrosis, a non-apoptotic cell death pathway. Strategies sensitizing brain tumor-derived EC to IR may enhance the efficacy of radiotherapy and EGCg may represent such a potential agent.

Apoptosis↗

PubMed2006

The Survivin-mediated radioresistant phenotype of glioblastomas is regulated by RhoA and inhibited by the green tea polyphenol (-)-epigallocatechin-3-gallate.

INTRODUCTION: Glioblastoma multiforme's (GBM) aggressiveness is potentiated in radioresistant tumor cells. The combination of radiotherapy and chemotherapy has been envisioned as a therapeutic approach for GBM. The goal of this study is to determine if epigallocatechin-3-gallate (EGCg), a green tea-derived anti-cancer molecule, can modulate GBMs' response to ionizing radiation (IR) and whether this involves mediators of intracellular signaling and inhibitors of apoptosis proteins. MATERIAL AND METHODS: U-87 human GBM cells were cultured and transfected with cDNAs encoding for Survivin, RhoA or Caveolin-1. Mock and transfected cells were irradiated at sublethal single doses. Cell proliferation was analyzed by nuclear cell counting. Apoptosis was detected using a fluorometric caspase-3 assay. Analysis of protein expression was accomplished by Western immunoblotting. RESULTS: IR (10 Gy) reduced control U-87 cell proliferation by 40% through a caspase-independent mechanism. The overexpression of Survivin induced a cytoprotective effect against IR, while the overexpression of RhoA conferred a cytosensitizing effect upon IR. Control U-87 cells pretreated with EGCg exhibited a dose-dependent decrease in their proliferation rate. The growth inhibitory effect of EGCg was not antagonized by overexpressed Survivin. However, Survivin -transfected cells pretreated with EGCg became sensitive to IR, and their RhoA expression was downregulated. A potential therapeutic effect of EGCg targeting the prosurvival intracellular pathways of cancer cells is suggested to act synergistically with IR. CONCLUSION: The radioresistance of GBM is possibly mediated by a mechanism dependent on Survivin in conjunction with RhoA. The combination of natural anti-cancerous molecules such as EGCg with radiotherapy could improve the efficacy of IR treatments.

Anticarcinogenic Agents↗

PubMed2006

Statins reduce human blood-brain barrier permeability and restrict leukocyte migration: relevance to multiple sclerosis.

OBJECTIVE: Dysregulation of the blood-brain barrier (BBB) and transendothelial migration of immune cells are among the earliest central nervous system changes partaking in lesion formation in both multiple sclerosis (MS) and its early clinical form, the clinically isolated syndrome. Evidence for the anti-inflammatory effects of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors within the central nervous system arose from studies demonstrating that statins improve clinical signs in the animal model of MS and reduce the number of gadolinium-enhancing lesions in MS. METHODS: We sought to describe the impact of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor treatment on the physiology and immunology of human BBB-derived endothelial cells (ECs). RESULTS: We demonstrate that lovastatin and simvastatin induce a 50 to 60% reduction in the diffusion rates of bovine serum albumin and [(14)C]-sucrose across human BBB-ECs in vitro through abrogation of isoprenylation processes, but independent of the expression of the tight junction molecules occludin, VE-cadherin, JAM-1, zonula occluden-1, and zonula occluden-2. Simvastatin and lovastatin were equipotent in reducing BBB permeability in vitro, with median effective concentration (EC(50)) of 9.5 x 10(-8) and 1.0 x 10(-7)M, respectively. We further demonstrate that lovastatin and simvastatin treatment of BBB-ECs significantly restricts the migration of clinically isolated syndrome-derived and MS-derived monocytes and lymphocytes across the human BBB in vitro, through a specific reduction in the secretion of the chemokines monocyte chemotactic protein-1/CCL2 and interferon-gamma-inducible protein-10/CXCL10 by BBB-ECs. INTERPRETATION: Our data parallel the previously reported magnetic resonance imaging-based radiological findings and suggest an effect of statins that could be beneficial in early MS, restricting the diffusion of molecular tracers and the migration of immune cells across the human BBB.

Adult↗

PubMed2006

A comparison between scalp nerve block and morphine for transitional analgesia after remifentanil-based anesthesia in neurosurgery.

We compared transitional analgesia provided by scalp nerve block (SNB) or morphine after remifentanil-based anesthesia in neurosurgery. Fifty craniotomy patients were randomly divided into two groups: morphine (morphine 0.1 mg x kg(-1) IV after dural closure and an SNB performed with 20 mL of 0.9% saline at the end of surgery) and block (10 mL of 0.9% saline instead of morphine after dural closure and an SNB performed with a 1:1 mixture of bupivacaine 0.5% and lidocaine 2% at the end of surgery). Postoperative pain was assessed at 1, 2, 4, 8, 12, 16, and 24 h using a 10-point numerical rating scale. Analgesia consisted of subcutaneous codeine. Average numerical rating scale scores were similar between the two groups at each time interval. Total codeine dosage was also similar, except at 4 h postoperatively when it was higher in the block group. The delay before administration of the first dose of codeine was not statistically different between groups: 45 min (20-2880) vs 30 min (10-2880), median and range for the block and morphine group, respectively. Postoperative hemodynamics were similar for both groups. The incidence of nausea and vomiting was slightly more frequent in the morphine group, but the occurrence of confusion did not differ between groups. In conclusion, SNB provides a quality of transitional analgesia that is similar to that of morphine with the same postoperative hemodynamic profile.

Adult↗

PubMed2005

Probing the infiltrating character of brain tumors: inhibition of RhoA/ROK-mediated CD44 cell surface shedding from glioma cells by the green tea catechin EGCg.

Glioma cell-surface binding to hyaluronan (HA), a major constituent of the brain extracellular matrix (ECM) environment, is regulated through a complex membrane type-1 matrix metalloproteinase (MT1-MMP)/CD44/caveolin interaction that takes place at the leading edges of invading cells. In the present study, intracellular transduction pathways required for the HA-mediated recognition by infiltrating glioma cells in brain was investigated. We show that the overexpression of the GTPase RhoA up-regulated MT1-MMP expression and triggered CD44 shedding from the U-87 glioma cell surface. This potential implication in cerebral metastatic processes was also observed in cells overexpressing the full-length recombinant MT1-MMP, while the overexpression of a cytoplasmic domain truncated from of MT1-MMP failed to do so. This suggests that the cytoplasmic domain of MT1-MMP transduces intracellular signaling leading to RhoA-mediated CD44 shedding. Treatment of glioma cells with the Rho-kinase (ROK) inhibitor Y27632, or with EGCg, a green tea catechin with anti-MMP and anti-angiogenesis activities, antagonized both RhoA- and MT1-MMP-induced CD44 shedding. Conversely, overexpression of recombinant ROK stimulated CD44 release. Taken together, our results suggest that RhoA/ROK intracellular signaling regulates MT1-MMP-mediated CD44 recognition of HA. These molecular processes may partly explain the diffuse brain-infiltrating character of glioma cells within the surrounding parenchyma and thus be a target for new approaches to anti-tumor therapy.

Brain Neoplasms↗

PubMed2005

Expression and activity of l-isoaspartyl methyltransferase decrease in stage progression of human astrocytic tumors.

Protein l-isoaspartyl methyltransferase (PIMT) functions as a repair enzyme that acts upon damaged proteins bearing abnormal aspartyl residues. We previously reported that PIMT expression and activity are reduced by half in human epileptic hippocampus. Here we investigated PIMT regulation in astrocytic tumors, which are the most common human brain tumors. PIMT expression and enzyme activity were significantly decreased in all grades of human astrocytic tumors. More precisely, PIMT levels were significantly lower by 76% in pilocytic astrocytomas (grade I), 46% in astrocytomas (grade II), 69% in anaplastic astrocytomas (grade III), and a marked 80% in glioblastomas (grade IV) as compared to normal brains. RT-PCR analysis showed that levels of type I PIMT mRNA were up-regulated while those of type II PIMT mRNA were down-regulated in glioblastomas. Furthermore, the reduced PIMT levels correlated closely with a decrease in the number of neuron cells in astrocytic tumors as assessed by measuring the neuron-specific enolase level. Many proteins with abnormal aspartyl residues accumulated in brain tumors and some were specific to individual grades of astrocytic tumors. Similar results were obtained, either by measuring the reduction in PIMT activity and expression or by measuring the formation of abnormal proteins, in an orthotopic rat brain tumor model implanted with invasive CNS-1 glioma cells. The novelty of these findings was to provide the first evidence for a marked reduction of PIMT expression and activity during stage progression of astrocytic tumors in humans.

Animals↗

PubMed2005

Cisatracurium-induced neuromuscular blockade is affected by chronic phenytoin or carbamazepine treatment in neurosurgical patients.

The effect of chronic anticonvulsant therapy (CAT) on the maintenance and recovery profiles of cisatracurium-induced neuromuscular blockade has not been adequately studied. In this study, we compared the pharmacokinetics and pharmacodynamics of cisatracurium after a prolonged infusion in patients with or without CAT. Thirty patients undergoing intracranial surgery were enrolled in the study: 15 patients under CAT (carbamazepine and phenytoin, Group A) and 15 controls receiving no anticonvulsant therapy (Group C). Anesthesia was standardized and both groups received a bolus of cisatracurium followed by an infusion to maintain a 95% twitch depression. A steady-state was obtained and the infusion was kept constant for 2 additional hours. Neuromuscular blockade was then allowed to spontaneously recover. Blood samples were taken for measurement of cisatracurium plasma concentration during the steady-state period (Cp(ss)95) and at various times during recovery. Demographic and intraoperative data were similar. CAT resulted in faster 25% and 75% recovery of the first twitch. The rate of infusion of cisatracurium needed to maintain a 95% twitch depression at steady-state was 44% faster in Group A (P < 0.001). The clearance of cisatracurium was significantly faster in Group A when compared with Group C (7.12 +/- 1.87 versus 5.72 +/- 0.70 L . kg(-1) . min(-1), P = 0.01). The Cp(ss)95 was also significantly larger in Group A (191 +/- 45 versus 159 +/- 36 ng/mL, P = 0.04). In addition, patients receiving CAT had a 20% increase in the clearance of cisatracurium that, in turn, resulted in a faster recovery of neuromuscular blockade after an infusion of the drug. Also, patients under CAT had a 20% increase in their Cp(ss)95, indicating an increased resistance to the effect of cisatracurium.

Adolescent↗

PubMed2004

Hyaluronan cell surface binding is induced by type I collagen and regulated by caveolae in glioma cells.

Hyaluronan (HA) is a component of the brain extracellular matrix environment that is synthesized and secreted by glioma cells. The primary cell surface receptor for HA is CD44, a membrane glycoprotein that is functionally regulated by a membrane type 1 matrix metalloproteinase (MT1-MMP). Both CD44 and MT1-MMP are partially located in Triton X-100-insoluble domains, but no functional link has yet been established between them. In the present study, we studied the regulation of HA cell surface binding in U-87 glioma cells. We show that an MMP-dependent mechanism regulates the intrinsic cell surface binding of HA as ilomastat, a broad MMP inhibitor, increased HA binding to glioma cells. HA binding was also rapidly and specifically up-regulated by 3-fold by type I collagen in U-87 cells, which also induced a significant morphological reorganization associated with the activation of a latent form of MMP-2 through a MT1-MMP-mediated mechanism. Interestingly, caveolae depletion with a cell surface cholesterol-depleting agent beta-cyclodextrin triggered an additional increase (9-fold) in the binding of HA, in synergy with type I collagen. On the other hand, HA cell surface binding was diminished by the MEK inhibitor PD98059 and by the overexpression of a recombinant, wild type MT1-MMP, whereas its cytoplasmic-deleted form had no effect. Taken together, our results suggest that MT1-MMP regulates, through its cytoplasmic domain, the cell surface functions of CD44 in a collagen-rich pericellular environment. Additionally, we describe a new molecular mechanism regulating the invasive potential of glioma cells involving a MT1-MMP/CD44/caveolin interaction, which could represent a potential target for anti-cancer therapies.

Caveolae↗

PubMed2004

Down-regulation of caveolin-1 in glioma vasculature: modulation by radiotherapy.

Primary brain tumors, particularly glioblastomas (GB), remain a challenge for oncology. An element of the malignant brain tumors' aggressive behavior is the fact that GB are among the most densely vascularized tumors. To determine some of the molecular regulations occuring at the brain tumor endothelium level during tumoral progression would be an asset in understanding brain tumor biology. Caveolin-1 is an essential structural constituent of caveolae that has been implicated in mitogenic signaling, oncogenesis, and angiogenesis. In this work we investigated regulation of caveolin-1 expression in brain endothelial cells (ECs) under angiogenic conditions. In vitro, brain EC caveolin-1 is down-regulated by angiogenic factors treament and by hypoxia. Coculture of brain ECs with tumoral cells induced a similar down-regulation. In addition, activation of the p42/44 MAP kinase is demonstrated. By using an in vivo brain tumor model, we purified ECs from gliomas as well as from normal brain to investigate possible regulation of caveolin-1 expression in tumoral brain vasculature. We show that caveolin-1 expression is strikingly down-regulated in glioma ECs, whereas an increase of phosphorylated caveolin-1 is observed. Whole-brain radiation treatment, a classical way in which GB is currently being treated, resulted in increased caveolin-1 expression in tumor isolated ECs. The level of tumor cells spreading around newly formed blood vessels was also elevated. The regulation of caveolin-1 expression in tumoral ECs may reflect the tumoral vasculature state and correlates with angiogenesis kinetics.

Angiogenic Proteins↗

PubMed2004

The effect of propofol sedation on the intracranial pressure of patients with an intracranial space-occupying lesion.

The fear of producing CO(2) retention and a secondary increase of intracranial pressure (ICP) sometimes precludes the use of sedation for the spontaneously breathing patient in the presence of an intracranial space-occupying lesion. In this study we assessed the effect of moderately deep propofol sedation on the ICP of patients undergoing stereotactic brain tumor biopsy under regional anesthesia. Thirty patients were randomized into 2 groups to receive propofol titrated to a level of 2 on the Observer's Assessment of Alertness/Sedation Scale or no sedation. ICP was measured via the biopsy needle. Preoperative data were similar in both groups. During surgery, patients receiving propofol had a higher arterial Pco(2) (48 +/- 8 mm Hg versus 41 +/- 3 mm Hg; P = 0.005) (95% confidence interval, 43-53 mm Hg and 39-43 mm Hg, respectively), resulting in a lower arterial pH (P = 0.002) than patients in the no-sedation group. The median ICP (95% confidence interval) for both groups was similar-13 mm Hg (8.2-16.2 mm Hg) and 15 mm Hg (8.3-21.7 mm Hg)-for the propofol and no-sedation groups, respectively (P = 0.66). Cerebral perfusion pressure was lower in the propofol group (76 +/- 18 mm Hg versus 89 +/- 18 mm Hg; P = 0.003). Moderately deep propofol sedation does not result in a higher ICP than no sedation in patients undergoing stereotactic brain tumor biopsy. Further studies are needed to assess the effect on ICP of other sedative medications.

Aged↗

PubMed2004

Chorioretinal atrophy in a patient with moyamoya disease. Case report.

Moyamoya disease is characterized by constrictions of segments of the internal carotid arteries (ICAs) and a resultant abnormal anastomotic network. In the literature, visual disturbances from cerebrovascular accidents in patients with moyamoya disease have been described, but very few reports of intraocular pathological conditions have been published. The authors describe a patient with moyamoya disease who presented with chorioretinal atrophy; an association between these two diseases has not previously been reported in the literature. Findings of a clinical ophthalmological evaluation and angiographic series are presented. During the fundic examination, evidence of chorioretinal atrophy was found in this patient. Choroidal vascular insufficiency was revealed by intravenous fluorescein angiography and occlusion of the ICAs proximal to the origin of the posterior communicating arteries by selective carotid and vertebral arteriography. The vertebrobasilar system provided anastomotic connections via the posterior communicating arteries. This is the first case report of chorioretinal atrophy associated with moyamoya disease. It is believed that the vasoocclusive effects of moyamoya disease may predispose the patient to atrophic changes in the peripheral retina. The development of an anastomotic network precludes the progression of this fundic anomaly.

Adult↗

PubMed2003

Paraspinous muscle flaps for the treatment and prevention of cerebrospinal fluid fistulas in neurosurgery.

STUDY DESIGN: A prospective clinical study was conducted to evaluate the efficacy of paraspinous muscle flaps in preventing and managing cerebrospinal fluid fistulas in high-risk neurosurgery patients. OBJECTIVES: To evaluate the efficacy of paraspinous muscle flap coverage using a "vest-over-pants" closure in the prevention and treatment of cerebrospinal fluid fistulas. SUMMARY OF BACKGROUND DATA: Previous studies have described paraspinous muscle flaps for the closure of complex spinal wounds, but none has addressed their use for the prevention and treatment of cerebrospinal fluid fistulas. METHODS: This prospective clinical study evaluated nine consecutive patients with either refractory cerebrospinal fluid fistulas or high risk for cerebrospinal fluid leaks after spinal surgery. Bilateral paraspinous muscle flaps were used as primary flaps and closed using an overlapping vest-over-pants technique in eight of nine cases. The latissimus dorsi and trapezius muscles were recruited as additional muscle flaps for closure of thoracolumbar and high thoracic deficits, respectively. RESULTS: Paraspinous muscle flaps provided immediate wound coverage in seven high-risk patients undergoing spinal surgery and two patients with recurrent cerebrospinal fluid fistulas. Postoperative hospitalization averaged 14.4 days. There was no evidence of a cerebrospinal fluid fistula after an average follow-up of 176.7 days. No wound infections occurred. The only complications were a superficial hematoma, which was drained percutaneously on postoperative day 6, and a seroma, which was drained during the follow-up period and eventually resolved. CONCLUSIONS: Paraspinous muscle flaps allow effective treatment and prevention of cerebrospinal fluid fistulas in selected high-risk patients and provide simple durable coverage of complex spinal wounds with minimal morbidity.

Adult↗

PubMed2003

Differences in multidrug resistance phenotype and matrix metalloproteinases activity between endothelial cells from normal brain and glioma.

Endothelial cells (ECs) are new targets for tumor therapy. In this work, we purified endothelial cells from intracerebral and subcutaneous experimental gliomas as well as from normal brain in order to define some of the phenotypical differences between angiogenic and quiescent brain vasculature. We show that the multidrug resistance genes encoding drug efflux pumps at the brain endothelium are expressed differently in normal and tumoral vasculature. We also show that ECs from gliomas present increased activity of gelatinase B (MMP9), key enzyme in the angiogenic process. Importantly, we observe a different phenotype between ECs in the intracerebral and subcutaneous models. Our results provide molecular evidence of phenotypic distinction between tumoral and normal brain vasculature and indicate that the EC phenotype depends on interactions both with tumor cells and also with the microenvironment.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed2002

The expression of rho proteins decreases with human brain tumor progression: potential tumor markers.

Astrocytic tumors are the most common human brain tumors. Establishment of tumor grade is a key determinant both in the choice of a therapeutic approach and in the prognosis. The diagnosis of astrocytic tumors is currently determined following histopathological analysis. The identification of molecular markers would offer a complementary tool for characterizing tumors with respect to their clinical behavior. In this study we determined the expression levels of 3 small GTP binding proteins (RhoA, RhoB and Rac1), of their inhibitor RhoGDI and of caveolin-1 in 24 human astrocytic tumors of grades I to IV. Our results demonstrated that the expression of RhoA and RhoB decreased significantly in all brain tumors studied and was inversely related with tumor of grade II to IV malignancy. The amount of caveolin-1 immunodetected was not significantly different from normal brain samples while the Rac1 expression level was diminished in astrocytic tumors of grades III and IV. Our finding that RhoA and RhoB expression levels are correlated to tumor malignancy suggests that they may serve as novel and efficient diagnostic markers for astrocytic brain tumors of histological grade II to IV and complement currently applied histopathological analysis.

Astrocytoma↗

PubMed2002

Differential regulation of matrix metalloproteinase activities in abdominal aortic aneurysms.

BACKGROUND: The increased synthesis of matrix metalloproteinases (MMPs) by aortic smooth muscle cells (SMCs) is thought to be involved in the etiopathogenesis of abdominal aortic aneurysms (AAAs), but the functional regulation and the activation states of these MMPs remain unclear. In this study, we assessed the expression levels and the functional regulation of several MMPs in the pathogenesis of AAAs. METHODS: Human healthy aorta and AAA specimens were homogenized, and the proteolytic activities of MMP-2 and MMP-9 and of the macrophage metalloelastase (MMP-12) were assessed with zymography. Protein expression of MMP-1, MMP-12, membrane-type 1 MMP (MT1-MMP), tissue inhibitor of MMP 1 (TIMP-1), TIMP-2, TIMP-3, alpha-actin, and beta-actin was analyzed with electrophoresis on sodium dodecyl sulfate gels and immunoblotting. RESULTS: MMP-1, MMP-9, and MMP-12 zymogen levels and proteolytic activities were increased in AAAs when compared with healthy aorta. A severe reduction in alpha-actin--positive vascular SMCs was observed in all the AAA specimens and was correlated with an increase in TIMP-3 but not TIMP-1 or TIMP-2 potential activities. Although pro--MMP-2 activity was decreased, the extent of activated MMP-2 remained unaffected in the AAAs. In accordance with this result, a highly activated MT1-MMP form was also observed in AAAs. CONCLUSION: These data suggest that chronic aortic wall inflammation is mediated by macrophage infiltration, which may account for the destruction of medial elastin, as reflected by SMC down regulation, through increased levels of active MMP-1 and MMP-12. Moreover, altered MT1-MMP proteolytic turnover and differential regulation of TIMP expression in AAAs suggest that tight regulatory mechanisms are involved in the molecular regulation of MMP activation processes in the pathogenesis of AAAs.

Actins↗