Taking Heart with Thymosin β4

Abstract

People who survive a heart attack often develop chronic heart disease because of the limited ability of the heart to repair damage by replacing lost cells. Noting that thymosin β4 (which stimulates cell migration, skin wound healing, and angiogenesis) is expressed in the developing cardiovascular system, Bock-Marquette et al. investigated the possibility that this G-actin-sequestering protein could be used to promote regeneration of damaged cardiac tissues (see Schneider). Thymosin β4 mRNA and protein were expressed in regions of the developing mouse heart that were rich in migratory cells. Thymosin β4 was secreted by transfected Cos1 cells, and thymosin β4 expressed on the surface of phage particles was internalized by cells in embryonic cardiac explants. Thymosin β4 promoted the in vitro migration of embryonic endothelial and myocardial cells, as well as the in vitro migration and survival of neonatal cardiomyocytes. Thymosin β4 bound to the LIM domain protein PINCH [which binds to integrin-linked kinase (ILK) as part of the focal adhesion kinase] and immunoprecipitated together with PINCH and ILK. Moreover, exposure to thymosin β4 or transfection with a thymosin β4-expressing plasmid increased ILK content and promoted phosphorylation of the ILK substrate Akt in C2C12 myoblasts. Administration of thymosin β4 also increased ILK content and Akt phosphorylation in heart extracts from mice subjected to coronary artery ligation to elicit a myocardial infarction, as well as reducing the size of the scar and improving cardiac function. Thus, the authors propose that thymosin β4 and the pathway it regulates may provide a new means of therapeutic intervention to ameliorate cardiac damage. I. Bock-Marquette, A. Saxena, M. D. White, J. M. DiMalo, D. Srivastava, Thymosin β4 activates integrin-linked kinase and promotes cardiac cell migration, survival and cardiac repair. Nature 432 , 466-472 (2004). [Online Journal] M. D. Schneider, Prometheus unbound. Nature 432 , 451-453 (2004). [Online Journal]