Alterations in membrane type-1 matrix metalloproteinase abundance after the induction of thoracic aortic aneurysm in a murine model

Jones, Jeffrey A.; Ruddy, Jean Marie; Bouges, Shenikqua; Zavadzkas, Juozas A.; Brinsa, Theresa A.; Stroud, Robert E.; Mukherjee, Rupak; Spinale, Francis G.; Ikonomidis, John S.

doi:10.1152/ajpheart.00028.2010

Cited by 26 publications

(32 citation statements)

References 41 publications

(60 reference statements)

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“…15,42,43 Adventitial CaCl 2 exposure is an established model of thoracic 32,33 and AAAs, 44 and as we and others have shown, is associated with early activation of MMP2 and aberrant ECM degradation. 44,45 By using these 2 distinct models of aortic remodeling and aneurysm, we studied the comparative role of MMP2 in constructive versus destructive remodeling of the aortic ECM. Here, we report that in addition to serving as a potent ECM protease, MMP2 is a key factor for optimal ECM synthesis in the aortic wall through activation of latent TGFβ1 and the downstream Smad2/3 pathway.…”

Section: Discussionmentioning

confidence: 99%

Divergent Roles of Matrix Metalloproteinase 2 in Pathogenesis of Thoracic Aortic Aneurysm

Shen

Lee

Basu

et al. 2015

ATVB

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Objective-Aortic aneurysm, focal dilation of the aorta, results from impaired integrity of aortic extracellular matrix (ECM).Matrix metalloproteinases (MMPs) are traditionally known as ECM-degrading enzymes. MMP2 has been associated with aneurysm in patients and in animal models. We investigated the role of MMP2 in thoracic aortic aneurysm using 2 models of aortic remodeling and aneurysm. Approach and Results-Male 10-week-old MMP2-deficient (MMP2 −/− ) and wild-type mice received angiotensin II (Ang II, 1.5 mg/kg/day) or saline (Alzet pump) for 4 weeks. Although both genotypes exhibited dilation of the ascending aorta after Ang II infusion, MMP2 −/− mice showed more severe dilation of the thoracic aorta and thoracic aortic aneurysm. The Ang II-induced increase in elastin and collagen (mRNA and protein) was markedly suppressed in MMP2 −/− thoracic aorta and smooth muscle cells, whereas only mRNA levels were reduced in MMP2 −/− -Ang II abdominal aorta. Consistent with the absence of MMP2, proteolytic activities were lower in MMP2 −/− -Ang II compared with wild-type-Ang II thoracic and abdominal aorta. MMP2-deficiency suppressed the activation of latent transforming growth factor-β and the Smad2/3 pathway in vivo and in vitro. Intriguingly, MMP2−/− mice were protected against CaCl 2 -induced thoracic aortic aneurysm, which triggered ECM degradation but not synthesis. Conclusions-This study reveals the dual role of MMP2 in ECM degradation, as well as ECM synthesis. Moreover, the greater susceptibility of the thoracic aorta to impaired ECM synthesis, compared with vulnerability of the abdominal aorta to aberrant ECM degradation, provides an insight into the regional susceptibility of the aorta to aneurysm development. Shen et al MMP2 and Thoracic Aortic Aneurysm 889ratio that reverses in the abdominal aorta. 26,27 Given the differential ECM composition and histological characteristics of the thoracic versus abdominal aorta, 15 MMP2 could play regionally distinct roles in remodeling of the aorta.In this study, we used 2 experimental models of aortic remodeling and aneurysm, Ang II infusion that triggers ECM synthesis, as well as degradation, and adventitial CaCl 2 exposure that only triggers ECM degradation. Ang II is a physiological hormone elevated in patients with cardiovascular diseases, [28][29][30] which leads to vascular remodeling, 31 whereas adventitial CaCl 2 exposure is an established experimental model of aortic aneurysm in rodents 32,33 and in large mammals. 34 The findings in this study reveal a dual function of MMP2 in ECM synthesis, as well as degradation, and differential susceptibility of the thoracic and abdominal aorta to reduced synthesis versus excess proteolysis of ECM proteins. Materials and MethodsMaterials and Methods are available in the online-only Data Supplement. Experimental Animals and ProceduresWild-type (WT; The Jackson Laboratory) and MMP2-deficient (MMP2 −/− ) 35 mice in C57BL/6 background received Ang II (SigmaAldrich) [36][37][38] or saline (control) for 4 weeks. Systolic blood p...

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Section: Discussionmentioning

confidence: 99%

Divergent Roles of Matrix Metalloproteinase 2 in Pathogenesis of Thoracic Aortic Aneurysm

Shen

Lee

Basu

et al. 2015

ATVB

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“…2 Key members of this family, including MMP-2 and Membrane Type-1 MMP (MT1-MMP), have played well-described roles in aneurysm development in both the abdomen and thorax. 3–6 Furthermore, substantial evidence implicating altered transforming growth factor-beta (TGF-β) signaling as a primary contributor to structural remodeling also exists. 5, 7, 8 However, the molecular mechanisms underlying the regulation of these processes continue to be elusive.…”

Section: Introductionmentioning

confidence: 99%

“…3, 6, 11, 12 Several unique characteristics of MT1-MMP contribute to its prescribed role as a master regulator of matrix remodeling. First, MT1-MMP has a diverse portfolio of proteolytic substrates and plays an integral role in mediating peri-cellular proteolysis at the cell-matrix interface.…”

Section: Introductionmentioning

confidence: 99%

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Regulation of membrane type-1 matrix metalloproteinase activity and intracellular localization in clinical thoracic aortic aneurysms

Ikonomidis

Nadeau

Akerman

et al. 2017

The Journal of Thoracic and Cardiovascular Surgery

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Objective Membrane type-1 MMP (MT1-MMP) is elevated during thoracic aortic aneurysm (TAA) development in mouse models, and plays an important role in the activation of MMP-2 and the release of matrix bound TGF-β. This study tested the hypothesis that MT1-MMP is subject to protein kinase C (PKC)-mediated regulation, which alters intracellular trafficking and activity with TAA. Methods Abundance of MMP-2, native and phosphorylated-MT1-MMP, and PKC-delta was measured in aortic tissue from patients with small TAAs (<5 cm; n=8) and large TAAs (>6.5 cm; n=8), and compared to normals (n=8). Cellular localization of green fluorescent protein-tagged MT1-MMP was assessed in aortic fibroblasts isolated from control and 4-week TAA mice. Effects of PKC-mediated phosphorylation on MT1-MMP cellular localization and function (active MMP-2 versus phospo-Smad-2 abundance), was determined following treatment with a PKC activator (phorbol-12-myristate-13-acetate; 100 nM) with and without a PKC-delta-specific inhibitor (Röttlerin, 3 µM). Results Compared to controls, MT1-MMP abundance increased in aortas from both TAA groups. Active MMP-2 was increased only in large TAAs. Abundance of phosphorylated MT1-MMP and activated-PKC-delta was enhanced in small versus large TAAs. MT1-MMP was localized on the plasma membrane in aortic fibroblasts from control mice and in endosomes from TAA mice. PMA treatment induced MT1-MMP-GFP internalization, enhanced phospho-Smad-2, and reduced MMP-2 activation, while Röttlerin pretreatment inhibited these effects. Conclusion Phosphorylation of MT1-MMP mediates its activity through directing cellular localization; shifting its role from MMP-2 activation to intracellular signaling. Targeted inhibition of MT1-MMP may therefore hold therapeutic relevance as a means to attenuate TAA development.

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“…Дело в том, что матрикс не только обеспечивает механическую под-держку клеток аорты, но и влияет на их функциональные свойства и фенотип [14]. В частности, показано, что сни-жение содержания эластина может приводить к увеличе-нию накопления коллагена и повышению жесткости сосудистой стенки [12].…”

Section: Discussionunclassified

Pathogenetic mechanisms of ascending aortic aneurysm of varied aetiology

Иртюга¹,

Гаврилюк²,

Воронкина³

et al. 2013

Russ J Cardiol

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Российский кардиологический журнал № 1 (99) | 2013По данным А. В. Покровского, частота выявления аневризм аорты в российской популяции составляет 0,16-1,06% [1]. Сходные результаты получены Р. Parsche и соавторами в крупном популяционном исследовании, в котором встречаемость аневризм аорты составила 0,77% [2]. В целом частота выявления аневризм груд-ного отдела аорты в общей популяции населения составляет 5,9 случаев на 100000 человек в год. Дальней-шие эпидемиологические исследования показали, что за период с 1982 по 2002 гг заболеваемость аневризмой грудного отдела аорты выросла в 2 раза [3]. По мнению экспертов, количество пациентов с патологией аорты будет неуклонно расти по мере увеличения продолжи-тельности жизни населения планеты. С учетом прогно-зируемого старения населения к 2030 году ожидается двукратное увеличение числа пациентов старше 65 лет, а, следовательно, можно предположить значительный рост распространенности аневризм грудного отдела аорты в общей популяции населения.С учетом высокой смертности среди пациентов с диссекцией аневризмы грудного отдела аорты, нередко достигающей 94-100%, а также высокой интраопера-ционной летальности, которая, несмотря на прогресс хирургической техники, в среднем составляет 25%, изучение патогенеза данной патологии и поиск опти-мальных методов профилактики имеет важное медико-социальное значение.Патогенетические механизмы, лежащие в основе формирования аневризмы восходящего отдела аорты, до сих пор остаются недостаточно изученными. При-близительно в 5% случаев расслоения восходящего отдела аорты выявляется синдром Марфана, моноген-ное наследственное заболевание соединительной ткани [4]. Возникает вопрос, можно ли объяснить генетиче-скими расстройствами формирование аневризм восхо-дящего отдела аорты у оставшихся 95% пациентов? В 2006 году в США начаты работы по созданию Нацио-нального регистра (GenTAC), цель которого на основе изучения моногенных и семейных случаев заболевания выявить генетические детерминанты, определяющие риск развития аневризмы восходящего отдела аорты и клинически значимых ее осложнений [5]. Вместе с тем, большинство аневризм аорты носят несиндром-ный спорадический характер, и выявление генетиче-ской предрасположенности у этой категории больных может существенно изменить тактику их ведения. Дело в том, что стратегию лечения больного на сегодняшний день определяет величина максимального размера аневризмы восходящего отдела аорты. В то же время существует мнение, что данный параметр не должен быть определяющим критерием в вопросе установле-ния показаний к профилактическому хирургическому лечению аневризмы аорты.На морфологическом уровне аневризма восходя-щего отдела аорты развивается, как результат патологи-ческого ремоделирования внеклеточного матрикса за счет нарушения состава или структуры основных его белков, а также за счет активного их протеолиза [6]. Однако открытым остается вопрос, существует ли связь между структурными изменениями восходящего отдела

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Alterations in membrane type-1 matrix metalloproteinase abundance after the induction of thoracic aortic aneurysm in a murine model

Cited by 26 publications

References 41 publications

Divergent Roles of Matrix Metalloproteinase 2 in Pathogenesis of Thoracic Aortic Aneurysm

Divergent Roles of Matrix Metalloproteinase 2 in Pathogenesis of Thoracic Aortic Aneurysm

Regulation of membrane type-1 matrix metalloproteinase activity and intracellular localization in clinical thoracic aortic aneurysms

Pathogenetic mechanisms of ascending aortic aneurysm of varied aetiology

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