Angiopoietin-1 Promotes Cardiac and Skeletal Myocyte Survival Through Integrins

Author:

Dallabrida Susan M.1,Ismail Nesreen1,Oberle Julianne R.1,Himes Blanca E.1,Rupnick Maria A.1

Affiliation:

1. 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.

Abstract

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 (Mn 2+ , Ca 2+ , not Mg 2+ ), 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 angiopoietin-1 phosphorylated Akt S473 and MAPK p42/44 , (not FAK Y397 ) in C2C12 more than in endothelial cells and more than did angiopoietin-2 or cell matrices. EDTA, RGD-based peptides, and some integrin antibodies blocked these responses. Angiopoietin-1 activated HSM and NCM Akt S473 and MAPK p42/44 survival pathways. We propose that this novel function contributes to developmental and cardioprotective actions of angiopoietin-1 presently attributed to vascular 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.

Publisher

Ovid Technologies (Wolters Kluwer Health)

Subject

Cardiology and Cardiovascular Medicine,Physiology

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