Atorvastatin Modulates Matrix Metalloproteinase Expression, Activity, and Signaling in Abdominal Aortic Aneurysms

Schweitzer, M.; Mitmaker, Benjamin; Obrand, Daniel; Sheiner, Nathan; Abraham, Cherrie; Dostanic, Stevan; Meilleur, Melissa; Sugahara, Tomoko; Chalifour, Lorraine E.

doi:10.1177/1538574409348352

Cited by 33 publications

(21 citation statements)

References 39 publications

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“…The apparent differences in the effects reported for different statins on MMPs regulation could be explained by methodological differences between studies or by differences in physicochemical properties of statins. Although lipophilic statins (simvastatin and atorvastatin) are expected to more likely penetrate extrahepatic cell membranes than the hydrophilic statins (pravastatin), it is acknowledged that lipophilicity does not entirely predict the ability of statins to exert pleiotropic effects (Schweitzer et al 2010;Corsini et al 1999). However, our findings support the notion that significant differences exist among statins.…”

Section: Discussionsupporting

confidence: 58%

Effects of statins on matrix metalloproteinases and their endogenous inhibitors in human endothelial cells

Izidoro-Toledo

Guimaraes

Belo

et al. 2011

Naunyn-Schmiedeberg's Arch Pharmacol

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Statins exert anti-inflammatory effects and downregulate matrix metalloproteinases (MMPs) expression, thus contributing to restore cardiovascular homeostasis in cardiovascular diseases. We aimed at comparing the effects of different statins (simvastatin, atorvastatin, and pravastatin) on MMP-2, MMP-9, tissue inhibitors of metalloproteinases (TIMP)-1, TIMP-2, and MMP-9/TIMP-1 and MMP-2/TIMP-2 ratios released by human umbilical vein endothelial cells (HUVEC) stimulated by phorbol myristate acetate (PMA). HUVECs were incubated with statins (0.1-10 μM) for 12 h before stimulation with PMA 100 nM. Monolayers were used to perform cell viability assays and the supernatants were collected to determine MMPs and TIMPs levels by gelatin zymography and/or enzyme immunoassay. While treatment with PMA increased MMP-9 and TIMP-1 levels (by 556% and 159%, respectively; both P < 0.05), it exerted no effects on MMP-2 and TIMP-2 levels. Simvastatin and atorvastatin, but not pravastatin, attenuated PMA-induced increases in MMP-9 levels (P < 0.05). Only atorvastatin decreased baseline MMP-2 levels significantly (P < 0.05). We found no effects on TIMP-2 levels. Simvastatin and atorvastatin, but not pravastatin, decreased MMP-9/TIMP-1 ratio significantly (both P < 0.05), whereas atorvastatin and pravastatin, but not simvastatin, decreased MMP-2/TIMP-2 ratio significantly (both P < 0.05). Our data support the notion that statins with different physicochemical features exert variable effects on MMP/TIMP ratios (which reflect net MMP activity). Our results suggest that more lipophilic statins (simvastatin and atorvastatin), but not the hydrophilic statin pravastatin, downregulate net MMP-9 activity. However, atorvastatin and pravastatin may downregulate net MMP-2 activity. The clinical implications of the present findings deserve further investigation.

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Section: Discussionsupporting

confidence: 58%

Effects of statins on matrix metalloproteinases and their endogenous inhibitors in human endothelial cells

Izidoro-Toledo

Guimaraes

Belo

et al. 2011

Naunyn-Schmiedeberg's Arch Pharmacol

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“…86,87 In several biological systems, statins have been shown to inhibit MMPs and increase TIMP-1. [88][89][90] These effects are likely induced by the inhibition of isoprenylation. Recently, we have shown that simvastatin inhibits both basal and IL-1a-induced expression of MMP-3 in human endometrial stromal cells.…”

Section: Statins In Treatment Of Endometriosismentioning

confidence: 99%

Novel Therapies Targeting Endometriosis

et al. 2011

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Endometriosis is an often painful disorder in which the endometrial glands and stroma grow outside the uterus. The disease affects women's quality of life and is a common cause of infertility. In this review, we describe promising new developments in the field based on in vitro assays and rodent models, each of which has the potential to be beneficial in the treatment of this disease. We will specifically describe the role of anti-inflammatory drugs, selective estrogen, or progesterone modulators, statins, antiangiogenic agents, and the potential for targeting stem cells as likely methods to hone in and eliminate endometriosis. The most promising of these potential therapies are currently slated for further testing in both rodent and nonhuman primate trials.

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“…In contrast to that, another study outlined the role of atorvastatin in the changes of MMP expression and signaling within abdominal aortic aneurysms. This study showed significantly reduced MMP-13 expression, a tendency toward reduced MMP-8 expression, and also a trend toward diminished TIMP-1 expression within aortic aneurysms [9]. Furthermore, MMP-1 concentrations tend to rise in more advanced coronary lesions, especially in patients with complex lesions [37], including patients with multivessel disease [5, 38].…”

Section: Collagenases (Mmp-1 Mmp-8 Mmp-13 and Mmp-18)mentioning

confidence: 99%

“…They are also implicated in the release of apoptotic signals and the activation or inactivation of many cytokines [8]. The extracellular MMP activity ranges from changes in cell-to-cell interactions, cell to ECM adhesions, cell survival, and proliferation to tissue composition and cell motility [8, 9]. …”

Section: Introductionmentioning

confidence: 99%

Matrix Metalloproteinases in Renal Diseases: A Critical Appraisal

Zakiyanov

Kalousová

Zima

et al. 2019

Kidney Blood Press Res

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Matrix metalloproteinases (MMPs) are endopeptidases within the metzincin protein family that not only cleave extracellular matrix (ECM) components, but also process the non-ECM molecules, including various growth factors and their binding proteins. MMPs participate in cell to ECM interactions, and MMPs are known to be involved in cell proliferation mechanisms and most probably apoptosis. These proteinases are grouped into six classes: collagenases, gelatinases, stromelysins, matrilysins, membrane type MMPs, and other MMPs. Various mechanisms regulate the activity of MMPs, inhibition by tissue inhibitors of metalloproteinases being the most important. In the kidney, intrinsic glomerular cells and tubular epithelial cells synthesize several MMPs. The measurement of circulating MMPs can provide valuable information in patients with kidney diseases. They play an important role in many renal diseases, both acute and chronic. This review attempts to summarize the current knowledge of MMPs in the kidney and discusses recent data from patient and animal studies with reference to specific diseases. A better understanding of the MMPs’ role in renal remodeling may open the way to new interventions favoring deleterious renal changes in a number of kidney diseases.

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Atorvastatin Modulates Matrix Metalloproteinase Expression, Activity, and Signaling in Abdominal Aortic Aneurysms

Cited by 33 publications

References 39 publications

Effects of statins on matrix metalloproteinases and their endogenous inhibitors in human endothelial cells

Effects of statins on matrix metalloproteinases and their endogenous inhibitors in human endothelial cells

Novel Therapies Targeting Endometriosis

Matrix Metalloproteinases in Renal Diseases: A Critical Appraisal

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