Thymosin Beta 4 Is Dispensable for Murine Cardiac Development and Function

Rationale: Thymosin beta 4 (T beta 4) is a 43-amino acid factor encoded by an X-linked gene. Recent studies have suggested that T beta 4 is a key factor in cardiac development, growth, disease, epicardial integrity, and blood vessel formation. Cardiac-specific short hairpin (sh)RNA knockdown of t beta 4 has been reported to result in embryonic lethality at E14.5-16.5, with severe cardiac and angiogenic defects. However, this shRNA t beta 4-knockdown model did not completely abrogate T beta 4 expression. To completely ablate T beta 4 and to rule out the possibility of off-target effects associated with shRNA gene silencing, further studies of global or cardiac-specific knockouts are critical. Objective: We examined the role of T beta 4 in developing and adult heart through global and cardiac specific t beta 4-knockout mouse models. Methods and Results: Global t beta 4-knockout mice were born at mendelian ratios and exhibited normal heart and blood vessel formation. Furthermore, in adult global t beta 4-knockout mice, cardiac function, capillary density, expression of key cardiac fetal and angiogenic genes, epicardial marker expression, and extracellular matrix deposition were indistinguishable from that of controls. Tissue-specific t beta 4-deficient mice, generated by crossing t beta 4-floxed mice to Nkx2.5-Cre and alpha MHC-Cre, were also found to have no phenotype. Conclusions: We conclude that T beta 4 is dispensable for embryonic viability, heart development, coronary vessel development, and adult myocardial function. (Circ Res. 2012;110:456-464.)