Selective MicroRNA Suppression in Human Thoracic Aneurysms

Jones, Jeffrey A.; Stroud, Robert E.; O'Quinn, Elizabeth C; Black, Laurel; Barth, Jeremy L.; Elefteriades, John A.; Bavaria, Joseph E.; Gorman, Joseph H.; Gorman, Robert C.; Spinale, Francis G.; Ikonomidis, John S.

doi:10.1161/circgenetics.111.960419

Cited by 104 publications

(75 citation statements)

References 37 publications

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“…Among MMPs, MMP2 is capable of degrading multiple ECM components, including collagen and elastin, 16,17 and has been strongly linked to excess ECM degradation in aneurysmal aorta as its levels are elevated in thoracic and abdominal aortic aneurysms (AAAs). [18][19][20][21][22][23][24] MMP2-deficient mice are protected against AAA in a model of adventitial CaCl 2 exposure 25 ; however the role of MMP2 in thoracic aortic aneurysm (TAA) has not yet been explored. Thoracic aorta consists of greater elastin lamellae layers and a greater elastin:collagen ratio that reverses in the abdominal aorta.…”

Section: See Accompanying Editorial On Page 752mentioning

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: See Accompanying Editorial On Page 752mentioning

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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“…Matrix metallopeptidase 2 (MMP2) is a direct target of miR-29 involved in cell proliferation, migration, invasion, and angiogenesis and also in human thoracic aneurysms (Cai et al 2014;Chen et al 2011;Fan et al 2013;Fang et al 2011;Jones et al 2011;Poudyal et al 2013;Presneau et al 2013;Steele et al 2010). miR-29 also regulates the expression of 3 MMPs, including MMP2, MMP14, and MMP15 in human fetal lung fibroblast cells ( Fig.…”

Section: Mir-29 Regulates the Expression Of Mmps Involved In Collagenmentioning

confidence: 99%

The role of miR-29 in pulmonary fibrosis

Cushing

Kuang

Lü

2015

Biochem. Cell Biol.

101

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Pulmonary fibrosis is a pathological condition in which lungs become scarred due to the excess extracellular matrix (ECM) deposition and structural alterations in the interstitium of lung parenchyma. Many patients with interstitial lung diseases (ILDs) caused by long-term exposure to toxic substances, chronic infections, or autoimmune responses develop fibrosis. Etiologies for many ILDs are unknown, such as idiopathic pulmonary fibrosis (IPF), a devastating, relentless form of pulmonary fibrosis with a median survival of 2-3 years. Despite several decades of research, factors that initiate and sustain the fibrotic response in lungs remain unclear and there is no effective treatment to block progression of fibrosis. Here we summarize recent findings on the antifibrotic activity of miR-29, a small noncoding regulatory RNA, in the pathogenesis of fibrosis by regulating ECM production and deposition, and epithelial-mesenchymal transition (EMT). We also describe interactions of miR-29 with multiple profibrotic and inflammatory pathways. Finally, we review the antifibrotic activity of miR-29 in animal models of fibrosis and highlight miR-29 as a promising therapeutic reagent or target for the treatment of pulmonary fibrosis.

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“…Thus, while the specificity of certain miRs in terms of mRNA targets remains to be fully developed, it is becoming apparent that certain miRs likely hold relevance to LV remodeling and to the ECM in particular. 45,59–61,140–142 For example, in a mouse model of MI, changes in relative myocardial miR-29a levels had distinct and directional effects on ECM remodeling in terms of myocardial fibrosis. 60 Other studies have provided direct evidence for a mechanistic relationship between relative miR-29a levels and MMP protein content.…”

Section: Mmp Proteolysis and Profibrosis: Two Sides Of The Same Coinmentioning

confidence: 99%

Membrane-Associated Matrix Proteolysis and Heart Failure

Spinale

Janicki²,

Zile³

2013

Circulation Research

Self Cite

144

138

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The extracellular matrix (ECM) is a complex entity containing a large portfolio of structural proteins, signaling molecules, and proteases. Changes in the overall integrity and activational state of these ECM constituents can contribute to tissue structure and function, which is certainly true of the myocardium. Changes in the expression patterns and activational states of a family of ECM proteolytic enzymes, the matrix metalloproteinases (MMPs), have been identified in all forms of LV remodeling and can be a contributory factor for the progression to heart failure. However, new clinical and basic research has identified some surprising and unpredicted changes in MMP profiles in LV remodeling processes, such as with pressure or volume overload, as well as with myocardial infarction. From these studies, it has become recognized that proteolytic processing of signaling molecules by certain MMP types, particularly the transmembrane MMPs, may actually facilitate ECM accumulation as well as modulate fibroblast transdifferentiation – both critical events in adverse LV remodeling. Based upon the ever increasing substrates and diversity of biological actions of MMPs, it is likely that continued research regarding the relationship of LV remodeling to this family of proteases will yield new insights into the ECM remodeling process itself as well as new therapeutic targets.

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Selective MicroRNA Suppression in Human Thoracic Aneurysms

Cited by 104 publications

References 37 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

The role of miR-29 in pulmonary fibrosis

Membrane-Associated Matrix Proteolysis and Heart Failure

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