Increased Circulating Tissue Inhibitor of Metalloproteinase-2 Is Associated With Resistant Hypertension.
Sabbatini Andrea R,Barbaro Natalia R,de Faria Ana Paula,Modolo Rodrigo,Ritter Alessandra Mileni V,Pinho Claudio,Amorim Rivadavio Fernandes Batista,Fontana Vanessa,Moreno Heitor
Journal of clinical hypertension (Greenwich, Conn.)
Resistant hypertension (RH) is associated with organ damage and cardiovascular risk. Evidence suggests the involvement of matrix metalloproteinase 2 (MMP-2) and tissue inhibitor of metalloproteinase 2 (TIMP-2) in hypertension and in cardiovascular remodeling. The aim of this study was to assess the levels of MMP-2 and TIMP-2 in RH and its relation with organ damage, including arterial stiffness and cardiac hypertrophy. MMP-2 and TIMP-2 levels were compared among 19 patients with normotension (NT), 116 with nonresistant hypertension (HTN) and 116 patients with resistant HTN (RH). MMP-2 levels showed no differences among NT, HTN, and RH groups, while TIMP-2 levels were higher in RH compared with HTN and NT groups (90.0 [76.1-107.3] vs 70.1 [57.7-88.3] vs 54.7 [40.9-58.1] ng/mL, P<.01), respectively. MMP-2/TIMP-2 ratio was reduced in the RH group compared with the HTN and NT groups (2.7 [1.9-3.4] vs 3.3 [2.6-4.2] vs 4.9 [4.5-5.3], P<.01), respectively. No associations were found between MMP-2 levels, TIMP-2, and MMP-2/TIMP-2 ratio with cardiac hypertrophy and arterial stiffness in the RH and HTN groups. Finally, in a regression analysis, reduced MMP-2/TIMP-2 ratio and increased TIMP-2 levels were independently associated with RH. The present findings provide evidence that TIMP-2 is associated with RH and might be a possible biomarker for screening RH patients.
10.1111/jch.12865
Effects of tissue inhibitor of metalloproteinase 2 deficiency on aneurysm formation.
Xiong Wanfen,Knispel Rebecca,Mactaggart Jason,Baxter B Timothy
Journal of vascular surgery
OBJECTIVE:Matrix metalloproteinase (MMP)-2 has been shown to play a pivotal role in aortic aneurysm formation. Its activation requires formation of a trimolecular complex of MMP-2, tissue inhibitor of metalloproteinase-2 (TIMP-2), and membrane type 1 (MT1)-MMP, which is attached to the cell surface. At higher concentrations, TIMP-2 becomes an inhibitor of MMP-2. Thus, TIMP-2 could both augment and inhibit matrix degradation. This study was undertaken to define the net effect of TIMP-2 on matrix destruction and aneurysm formation. METHODS:The abdominal aortas of wild-type and TIMP-2-deficient (TIMP-2 -/-) mice were exposed to 0.25 mol/L CaCl2 or 0.9% NaCl for 15 minutes after laparotomy. Aortic diameters were measured before treatment and 6 weeks after aneurysm induction. In addition, aortic tissues were studied for MMP-2 activation by zymography, and matrix structure was studied by connective tissue staining. RESULTS:The aortic diameter increased in both wild-type and TIMP-2-/- mice. The increase in the TIMP-2 -/- mice was significantly smaller after CaCl2 treatment (51% +/- 3%) compared with the diameter of wild-type mice (67% +/- 4%). Connective staining of aortic sections from the CaCl2-treated mice revealed disruption and fragmentation of the medial elastic lamellae in both wild-type and TIMP-2 -/- mice. Zymographic analysis showed that active MMP-2 levels were decreased in TIMP-2 -/- aortas compared with wild-type mice. CONCLUSIONS:Targeted deletion of TIMP-2 results in attenuation of aneurysm development. Despite its name as an inhibitor of MMPs, TIMP-2 promotes aortic enlargement in vivo, presumably through its role as a cofactor in the activation of MMP-2. CLINICAL RELEVANCE:Abdominal aortic aneurysmal (AAA) disease is a potentially fatal disorder that screening studies have detected in 2% to 9% of the general population. Medical therapy designed to inhibit the progression of small aneurysms includes control of hypertension and smoking cessation; neither of these measures is of proven benefit. Effective and directed medical treatments for small AAAs await elucidation of key etiologic factors. Understanding precisely which molecules mediate AAA development, and blocking the activity of these molecules, could lead to important new therapies. Through our research, we have found that tissue inhibitor of metalloproteinase (TIMP)-2 has a role in this process in an experimental model of aortic aneurysms. We believe that TIMP-2 promotes aortic enlargement in vivo by activating matrix metalloproteinase 2.
10.1016/j.jvs.2006.06.036
Expression of matrix metalloproteinases and tissue inhibitors of metalloproteinases in HTLV-I-associated myelopathy.
Umehara F,Okada Y,Fujimoto N,Abe M,Izumo S,Osame M
Journal of neuropathology and experimental neurology
Matrix metalloproteinases (MMPs) have been reported to be involved in inflammatory disorders of the central nervous system (CNS). However, little is known about the role of MMPs in the pathogenesis of HTLV-I-associated myelopathy (HAM)/Tropical spastic paraparesis (TSP). To address this issue, we examined the tissue expression and localization of MMPs and their inhibitors, tissue inhibitors of metalloproteinases (TIMPs) in the spinal cord lesions of HAM/TSP using immunohistochemistry. In addition, the blood and cerebrospinal fluid (CSF) levels of MMPs and TIMPs of the patients with HAM/TSP were determined using sandwich enzyme immunoassays (SIA) and gelatin zymography. Immunohistochemical studies revealed that collagen IV and decorin immunoreactivity on the basement membrane of CNS parenchymal vessels was partially disrupted where inflammatory mononuclear cells infiltrated in active-chronic lesions of HAM/TSP. In these lesions, MMP-2 (gelatinase A) was immunostained mainly on the surface of foamy macrophages and lymphocytes, whereas MMP-9 (gelatinase B) expression was positive in the intravascular and perivascular mononuclear cells but not on foamy macrophages. In contrast, inactive chronic lesions of the spinal cords of the HAM/TSP contained fewer MMP-2-positive or MMP-9-positive mononuclear cells than active-chronic lesions. Many parenchymal vessels had thickened vascular walls which showed increased immunoreactivity to decorin. SIA revealed that production levels of MMP-2 and MMP-9 in both blood and CSF were higher in the patients with HAM/TSP than those in non-inflammatory other neurological disease controls (ONDs). Using zymography, proMMP-9 was detected more frequently in the CSF of patients with HAM/TSP than those in ONDs. Taken together, our data indicate that MMP-2 and MMP-9 may play an important role in the blood-brain barrier breakdown and tissue remodeling in the CNS of HAM/TSP.
10.1097/00005072-199809000-00005
The roles of adhesion molecules and proteinases in lymphocyte transendothelial migration.
Madri J A,Graesser D,Haas T
Biochemistry and cell biology = Biochimie et biologie cellulaire
T cell extravasation into perivascular tissue during inflammation involves transmigration through the endothelial cell (EC) layer and basement membrane. We have demonstrated that matrix metalloxproteinase-2 (MMP-2) is induced in T cells upon adhesion to endothelial cells and that the induction of MMP-2 is mediated by binding of T cell VLA-4 to VCAM-1. Cloned murine Th1 cells antigenic to myelin basic protein, either expressing VLA-4 on their cell surface and causing experimental autoimmune encephalomyelitis (EAE) or not expressing VLA-4 and not causing EAE, were used. VLA-4 positive (+) T cells that adhered to VCAM-1 positive (+) endothelial cells exhibited an induction in MMP-2 mRNA, protein, and activity, whereas MMP-2 was not induced in the T cells that adhered to the VCAM-1 negative (-) endothelial cells or VLA-4 negative (-) T cells that adhered to VCAM-1+ endothelial cells. Incubating T cells with rVCAM-1-coated dishes showed that VLA-4+ T cells adhered to the molecule and that adhesion to rVCAM-1 was sufficient to induce MMP-2. VLA-4+ T cells that had transmigrated through a VCAM-1+ endothelial cell monolayer exhibited MMP-2 activity. TIMP-2 was shown to reduce T cell transmigration in vitro. Transmigrated T cells exhibited downregulation of VLA-4 and LFA-1 integrin surface expression and decreased binding to rVCAM-1 and rICAM-1 and increased binding to collagens I and IV, fibronectin, and laminin. Brain sections of mice demonstrated that as T cells migrated farther into the tissue, VLA-4 expression was lost, although CD4 expression remained unchanged. These results demonstrate that binding to VCAM-1 on endothelial cells induces MMP-2 in T cells, which, in turn, may facilitate T cell migration into perivascular tissue. The significance of these findings in the modulation of the inflammatory response is discussed.
Endogenous proteolytic activity in a rat model of spontaneous cerebral stroke.
Sironi Luigi,Maria Calvio Anna,Bellosta Stefano,Lodetti Barbara,Guerrini Uliano,Monetti Mara,Tremoli Elena,Mussoni Luciana
Brain research
We evaluated the expression of two extra-cellular protease systems in a model of spontaneous cerebrovascular pathology: spontaneously hypertensive stroke-prone rats (SHRSP). The appearance of brain damage in individual animals was imaged and followed by means of magnetic resonance imaging (MRI). In situ zymography of brain slices obtained 3 days after the appearance of brain damage showed an increase in plasminogen activator (PA)/plasmin activity that co-localised with the cerebral damage detected by MRI; there was also concomitant accumulation/activation of inflammatory cells in the damaged area. Proteolytic activity was inhibited by the urokinase-specific inhibitor amiloride but not by an antibody against tissue-type plasminogen activator (t-PA). SDS-PAGE zymography of brain extracts revealed the presence of 58 kDa plasminogen-dependent lysis areas in the ischemic and non-ischemic tissues, and a 33 kDa lysis area in ischemic tissue only. An antibody against t-PA inhibited the former, whereas the latter was inhibited by amiloride. The specific induction of urokinase-type plasminogen activator (u-PA) in the damaged tissue was further confirmed by the fact that both u-PA protein mass and mRNA were markedly increased in the damaged cerebral areas. Concomitant metalloproteinase-2 (MMP-2) activation was only observed in the damaged area. These data suggest that u-PA is expressed and selectively catalyses proteolysis in the injured area of spontaneous brain damage in SHRSP.
10.1016/s0006-8993(03)02578-2
TIMP-2: an endogenous inhibitor of angiogenesis.
Stetler-Stevenson William G,Seo Dong-Wan
Trends in molecular medicine
Remodeling of the extracellular matrix--regulated by the matrix metalloproteinases (MMPs) and their endogenous inhibitors--is an important component of disease progression in many chronic disease states. Unchecked MMP activity can result in significant tissue damage, facilitate disease progression and is associated with host responses to pathologic injury, such as angiogenesis. The tissue inhibitors of metalloproteinases (TIMPs) have been shown to regulate MMP activity. However, recent findings demonstrate that an MMP-independent effect of TIMP-2 inhibits the mitogenic response of human microvascular endothelial cells to growth factors. This is the first demonstration of a cell-surface signaling receptor for a member of the TIMP family and suggests that TIMP-2 functions to regulate cellular responses to growth factors. These new findings are integrated in a comprehensive model of TIMP-2 function in tissue homeostasis.
10.1016/j.molmed.2005.01.007
Molecular mechanisms of tissue inhibitor of metalloproteinase 2 in the tumor microenvironment.
Molecular and cellular therapies
There has been a recent paradigm shift in the way we target cancer, drawing a greater focus on the role of the tumor microenvironment (TME) in cancer development, progression and metastasis. Within the TME, there is a crosstalk in signaling and communication between the malignant cells and the surrounding extracellular matrix. Matrix metalloproteinases (MMPs) are zinc-dependent endoproteases that have the ability to degrade the matrix surrounding a tumor and mediate tumor growth, angiogenesis and metastatic disease. Their endogenous inhibitors, the Tissue Inhibitors of Metalloproteinases (TIMPs), primarily function to prevent degradation of the ECM via inhibition of MMPs. However, recent studies demonstrate that TIMP family members also possess MMP-independent functions. One TIMP member in particular, TIMP-2, has many distinct properties and functions, that occur independent of MMP inhibition, including the inhibition of tumor growth and reduction of angiogenesis through decreased endothelial cell proliferation and migration. The MMP-independent molecular mechanisms and signaling pathways elicited by TIMP-2 in the TME are described in this review.