Cardioprotection by Thymosin Beta 4.

Treatment with thymosin beta 4 (Tβ4) reduces infarct volume and preserves cardiac function in preclinical models of cardiac ischemic injury. These effects stem in part from decreased infarct size, but additional benefits are likely due to specific antifibrotic and proangiogenic activities. Injected or transgenic Tβ4 increase blood vessel growth in large and small animal models, consistent with Tβ4 converting hibernating myocardium to an actively contractile state following ischemia. Tβ4 and its degradation products have antifibrotic effects in in vitro assays and in animal models of fibrosis not related to cardiac injury. This large number of pleiotropic effects results from Tβ4's many interactions with cellular signaling pathways, particularly indirect regulation of cellular motility and movement via the SRF-MRTF-G-actin transcriptional pathway. Variation in effects and effect sizes in animal models may potentially be due to variable distribution of Tβ4. Preclinical studies of PK/PD relationships and a reliable pharmacodynamic biomarker would facilitate clinical development of Tβ4.