Published online before print February 3, 2005, doi: 10.1161/01.RES.0000158285.57191.60
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Submitted on May 18, 2004
Revised on January 24, 2005
Accepted on January 25, 2005
Angiopoietin-1 Promotes Skeletal and Cardiac Myocyte Survival Through Integrins
Susan M. Dallabrida ;
From the Division of Vascular Biology (S.M.D., N.I., J.R.O., B.E.H., M.A.R.), Children’s Hospital, Boston; Harvard-MIT Division of Health Sciences and Technology (B.E.H.), Cambridge; the Division of Cardiovascular Medicine (M.A.R.), Brigham and Women’s Hospital, Boston; and the Department of Chemical Engineering (M.A.R.), Massachusetts Institute of Technology, Cambridge, Mass.
* To whom correspondence should be addressed. E-mail: maria.rupnick{at}childrens.harvard.edu.
Cardiac myocyte loss, regardless of insult, can trigger compensatory myocardial remodeling leading to heart failure. Identifying mediators of cardiac myocyte survival may advance clinical efforts toward myocardial preservation. Angiopoietin-1 limits ischemia-induced cardiac injury. This benefit is ascribed to angiogenesis because the receptor, tie2, is largely endothelial-specific. We propose that direct, non-tie2 interactions of angiopoietin-1 on cardiac myocytes contribute to this cardioprotection. We found that mouse C2C12 skeletal myocytes lack tie2 yet dose-dependently adhered to angiopoietin-1 and angiopoietin-2 similarly to laminin, fibronectin, vitronectin, and more than to collagen-I, -III, and -IV. Adhesion was divalent cation-mediated (Mn2+, Ca2+, not Mg2+), blocked with EDTA/EGTA, RGD-based peptides, and select integrin subunit antibodies. Similar findings were obtained with human skeletal myocytes (HSMs) and freshly isolated rat neonatal cardiac myocytes (NCMs). Furthermore, angiopoietin-1 conferred significant survival advantage exceeding that of most cell matrices, which was not fully explained by differences in cell adhesion. Angiopoietin-1 promoted survival of serum-starved C2C12, HSM, and NCM (MTT, trypan blue) and prevented taxol-induced apoptosis (caspase-3). Immobilized and soluble Ang1 phosphorylated AktS473 and MAPKp42/44, (not FAKY397) in C2C12 more than in endothelial cells and more than did Ang2 or cell matrices. EDTA, RGD-based peptides, and some integrin antibodies blocked these responses. Angiopoietin-1 activated HSM and NCM AktS473 and MAPKp42/44 survival pathways. We propose that this novel function contributes to developmental and cardioprotective actions of angiopoietin-1 presently attributed to vasculature effects alone. Angiopoietin-1 may prove therapeutically valuable in cardiac remodeling by supporting myocyte viability and preserving pump function. The full text of this article is available online at http://circres.ahajournals.org.
Key words: angiopoietin-1 • angiopoietin-2 • cardiac myocytes • adhesion molecules • myocyte apoptosis • necrosis
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