Protection Against Myocardial Infarction and No-Reflow Through Preservation of Vascular Integrity by Angiopoietin-Like 4

被引：151

作者：

Galaup, Ariane ^{[1
,2
,3
,5
]}

Gomez, Elisa ^{[1
,2
,3
,4
,5
]}

Souktani, Rachid ^{[7
]}

Durand, Melanie ^{[1
,2
,3
,5
]}

Cazes, Aurelie ^{[1
,2
,3
,8
]}

Monnot, Catherine ^{[1
,2
,3
,5
]}

Teillon, Jeremie ^{[1
,2
,3
,4
,5
]}

Le Jan, Sebastien ^{[1
,2
,3
,9
]}

Bouleti, Claire ^{[1
,2
,3
,4
,5
]}

Briois, Gaelle ^{[1
,2
,3
,4
,5
]}

Philippe, Josette ^{[1
,2
,3
,4
,5
]}

Pons, Sandrine ^{[6
,7
]}

Martin, Valerie ^{[6
,7
]}

Assaly, Rana ^{[6
,7
]}

Bonnin, Philippe ^{[10
]}

Ratajczak, Philippe ^{[11
,12
]}

Janin, Anne ^{[11
,12
]}

Thurston, Gavin ^{[13
]}

Valenzuela, David M. ^{[13
]}

Murphy, Andrew J. ^{[13
]}

Yancopoulos, George D. ^{[13
]}

Tissier, Renaud ^{[6
,7
]}

Berdeaux, Alain ^{[6
,7
]}

Ghaleh, Bijan ^{[6
,7
]}

Germain, Stephane ^{[1
,2
,3
,5
,14
]}

机构：

[1] Coll France, CIRB, F-75005 Paris, France

[2] CNRS, UMR 7241, Paris, France

[3] INSERM, U1050, Paris, France

[4] Univ Paris 06, ED Physiol & Physiopathol 394, Paris, France

[5] Sci & Lettres Res Univ, MEMOLIFE Lab Excellence & Paris, Paris, France

[6] Hop Henri Mondor, INSERM, U955, Equipe 3, F-94010 Creteil, France

[7] Univ Paris Est, Fac Med, Creteil, France

[8] Hop Europeen Georges Pompidou, AP HP, Serv Anat Pathol, Paris, France

[9] Uppsala Univ, Dept Med Biochem & Microbiol, Uppsala, Sweden

[10] Hop Lariboisiere, AP HP, F-75475 Paris, France

[11] Hop St Louis, INSERM, U728, Paris, France

[12] Univ Paris 07, Paris, France

[13] Regeneron Pharmaceut Inc, Tarrytown, NY 10591 USA

[14] Hop Europeen Georges Pompidou, AP HP, Serv Hematol Biol A, Paris, France

来源：

CIRCULATION | 2012年 / 125卷 / 01期

关键词：

no-reflow; acute myocardial infarction; endothelial cells; vascular integrity; hypoxia; INDUCED ADIPOSE FACTOR; LIPOPROTEIN-LIPASE; EXPRESSION; PLASMA; ISCHEMIA; RECEPTOR; ANGPTL4; ANGIOGENESIS; PERMEABILITY; INHIBITION;

D O I：

10.1161/CIRCULATIONAHA.111.049072

中图分类号：

R5 [内科学];

学科分类号：

100201 [内科学];

摘要：

Background-Increased permeability, predominantly controlled by endothelial junction stability, is an early event in the deterioration of vascular integrity in ischemic disorders. Hemorrhage, edema, and inflammation are the main features of reperfusion injuries, as observed in acute myocardial infarction (AMI). Thus, preservation of vascular integrity is fundamental in ischemic heart disease. Angiopoietins are pivotal modulators of cell-cell junctions and vascular integrity. We hypothesized that hypoxic induction of angiopoietin-like protein 4 (ANGPTL4) might modulate vascular damage, infarct size, and no-reflow during AMI. Methods and Results-We showed that vascular permeability, hemorrhage, edema, inflammation, and infarct severity were increased in angptl4-deficient mice. We determined that decrease in vascular endothelial growth factor receptor 2 (VEGFR2) and VE-cadherin expression and increase in Src kinase phosphorylation downstream of VEGFR2 were accentuated after ischemia-reperfusion in the coronary microcirculation of angptl4-deficient mice. Both events led to altered VEGFR2/VE-cadherin complexes and to disrupted adherens junctions in the endothelial cells of angptl4-deficient mice that correlated with increased no-reflow. In vivo injection of recombinant human ANGPTL4 protected VEGF-driven dissociation of the VEGFR2/VE-cadherin complex, reduced myocardial infarct size, and the extent of no-reflow in mice and rabbits. Conclusions-These data showed that ANGPTL4 might constitute a relevant target for therapeutic vasculoprotection aimed at counteracting the effects of VEGF, thus being crucial for preventing no-reflow and conferring secondary cardioprotection during AMI. (Circulation. 2012; 125: 140-149.)

引用

页码：140 / U557

页数：26

共 52 条

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Task force 1: The ACCF and AHA codes of conduct in human subjects research [J].