Preoperative treatment with doxycycline reduces aortic wall expression and activation of matrix metalloproteinases in patients with abdominal aortic aneurysms

Curci, John A.; Mao, Dongli; Bohner, Diane G.; Allen, Bradley S.; Rubin, Brian G.; Reilly, Jeffrey M.; Sicard, Gregorio A.; Thompson, Robert W.

doi:10.1016/s0741-5214(00)90163-0

Cited by 207 publications

(163 citation statements)

References 66 publications

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“…However it is not completely understood if the reduced number of metastases is due to a direct e ect of tetracyclines on MMP synthesis or on tumor cell proliferation. In this context studies on chemically modi®ed tetracycline type inhibitors on MMPs have shown that while MMPs can indeed be directly inhibited at the levels of transcription (Curci et al, 2000;Hanemaaijer et al, 1998) and function (Smith et al, 1999;Sorsa et al, 1998), many tumor and normal cell lines show a tetracycline-mediated growth inhibition which may be independent of the MMP blockade (Bettany and Wolowacz, 1998;Sledge, 1995, 1998;van den Bogert et al, 1985). This might explain the observation that doxycycline, administered at 20 mg/kg/day, signi®cantly inhibited tumor growth of mammary carcinoma cells subcutaneously injected in athymic mice (Fife and Sledge, 1998).…”

Section: Discussionmentioning

confidence: 99%

“…Doxycycline belongs to the family of chemically modi®ed tetracyclines, which can suppress MMP activity in a variety of tissues and tumors (Sipos et al, 1994), as well as inhibit gelatinase activity in human breast carcinoma cells (Fife and Sledge, 1995). Although doxycycline has been considered a nonselective MMP inhibitor, published data suggest that this chemically modi®ed tetracycline seems to preferentially inhibit gelatinase B/MMP9 activity and expression in corneal epithelial (Sobrin et al, 2000) and human endothelial cells (Hanemaaijer et al, 1998), as well as reducing in vivo levels of MMP-9 in tissues from patients with thoracic aneurysms (Curci et al, 2000). These observations prompted us to analyse the e ect of doxycycline on MMP synthesis and consequent tumor vascularization in normal and a1-null mice.…”

Section: Introductionmentioning

confidence: 99%

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Low plasma levels of matrix metalloproteinase 9 permit increased tumor angiogenesis

2002

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Angiogenesis is essential for tumor growth and blocking this process might be a valid tool for the control of cancer growth. We showed previously that tumor angiogenesis in integrin a1-null mice is reduced compared to that of wild type animals and that over-expression of matrix metalloproteinase 9 (MMP-9) in the a1-null and consequent generation of angiostatin (an inhibitor of endothelial cell growth) from circulating plasminogen was implicated in the mechanism of tumor inhibition. Our ®ndings suggested that secretion of excess MMPs generates inhibitors of endothelial cell proliferation, including but not necessarily limited to angiostatin, resulting ultimately in auto-inhibition of angiogenesis. Thus MMP inhibitors used as anti-tumor drugs might in fact cause a paradoxical increase in tumor angiogenesis and tumor growth. In order to determine whether MMP-9 expression was directly involved in the regulation of tumor growth, we speci®cally inhibited or enhanced MMP-9 synthesis in vitro and in vivo, and subsequently analysed primary endothelial cell proliferation and angiostatin synthesis, as well as tumor vascularization and development. We provide evidence that reduction of plasma levels of MMP-9 in either normal or integrin a1-null mice leads to decreased synthesis of angiostatin and consequent increased tumor growth and vascularization. In contrast, speci®cally enhancing MMP-9 expression in vivo caused a reduction in tumor vascularization. These ®ndings are the opposite to other studies suggesting a pro-tumorigenic role for MMP-9, and may account for some of the recently observed failures of anti MMP therapy in tumor treatment.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Low plasma levels of matrix metalloproteinase 9 permit increased tumor angiogenesis

2002

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“…15,24,27,36,91 MMP-9 inhibitors have showed utility in protection from ICH. [92][93][94] Inhibiting MMP-9 may also negate the harmful effects of AVMrelated inflammatory responses. Lee et al 28,29 evaluated the effect of the MMP-9 inhibitors minocycline and pyrrolidine dithiocarbamate on an AVM mouse model and showed that MMP-9 blockade significantly reduced the extent of hemorrhage.…”

Section: Potential Therapeutic Targetsmentioning

confidence: 99%

Biology of Cerebral Arteriovenous Malformations with a Focus on Inflammation

Mouchtouris

Jabbour

Starke

et al. 2014

J Cereb Blood Flow Metab

128

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Cerebral arteriovenous malformations (AVMs) entail a significant risk of intracerebral hemorrhage owing to the direct shunting of arterial blood into the venous vasculature without the dissipation of the arterial blood pressure. The mechanisms involved in the growth, progression and rupture of AVMs are not clearly understood, but a number of studies point to inflammation as a major contributor to their pathogenesis. The upregulation of proinflammatory cytokines induces the overexpression of cell adhesion molecules in AVM endothelial cells, resulting in enhanced recruitment of leukocytes. The increased leukocyte-derived release of metalloproteinase-9 is known to damage AVM walls and lead to rupture. Inflammation is also involved in altering the AVM angioarchitecture via the upregulation of angiogenic factors that affect endothelial cell proliferation, migration and apoptosis. The effects of inflammation on AVM pathogenesis are potentiated by certain single-nucleotide polymorphisms in the genes of proinflammatory cytokines, increasing their protein levels in the AVM tissue. Furthermore, studies on metalloproteinase-9 inhibitors and on the involvement of Notch signaling in AVMs provide promising data for a potential basis for pharmacological treatment of AVMs. Potential therapeutic targets and areas requiring further investigation are highlighted.

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“…It has been documented that preoperative doxycycline treatment (for 7 days) in patients who underwent elective repair of an infrarenal AAA, reduced MMP-9 expression and post-translational processing of MMP-2 in aneurysmal tissues [76]. Interestingly, in a prospective phase II study (cohort n=36),…”

Section: Tetracyclinementioning

confidence: 98%

Emerging Pharmacological Treatments to Prevent Abdominal Aortic Aneurysm Growth and Rupture

Fraga‐Silva

Trachet²,

Stergiopulos³

2015

CPD

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Abdominal aortic aneurysm (AAA) is a local expansion of the abdominal aorta wall caused by a complex multifactorial maladaptive vascular remodeling. Despite recent advances in the management of cardiovascular diseases, there currently is no established drug therapy for AAA. Since the probability of death from a ruptured AAA still remains high, preventive elective repair of AAAs larger than 5.5 cm in luminal diameter is considered the best treatment option. However, perioperative complications are problematic as elective AAA repair comes with numerous intrinsic risks. Impelled by the need of improving AAA therapy, significant efforts have been made to identify pharmacological tools that would slow down AAA enlargement and lower the risk of rupture, thereby reducing the necessity of surgical intervention. In this review, we discuss recent findings addressing molecular targets that could potentially treat AAA, particularly addressing: statins, classical renin angiotensin system (RAS) blockers, the protective arm of RAS, renin inhibitors, tetracyclines, interleukin-1β inhibition, anti-angiogenic agents and urocortins.

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Preoperative treatment with doxycycline reduces aortic wall expression and activation of matrix metalloproteinases in patients with abdominal aortic aneurysms

Cited by 207 publications

References 66 publications

Low plasma levels of matrix metalloproteinase 9 permit increased tumor angiogenesis

Low plasma levels of matrix metalloproteinase 9 permit increased tumor angiogenesis

Biology of Cerebral Arteriovenous Malformations with a Focus on Inflammation

Emerging Pharmacological Treatments to Prevent Abdominal Aortic Aneurysm Growth and Rupture

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