Thymosin β4 Is Cardioprotective after Myocardial Infarction

Abstract

Heart disease is a leading cause of death in newborns and in adults. Efforts to promote cardiac repair by introduction or recruitment of exogenous stem cells hold promise but typically involve isolation and introduction of autologous or donor progenitor cells. We have found that the G-actin-sequestering peptide thymosin beta4 promotes myocardial and endothelial cell migration in the embryonic heart and retains this property in postnatal cardiomyocytes. Survival of embryonic and postnatal cardiomyocytes in culture was also enhanced by thymosin beta4. We found that thymosin beta4 formed a functional complex with PINCH and integrin-linked kinase (ILK), resulting in activation of the survival kinase Akt/PKB, which was necessary for thymosin beta4's effects on cardiomyocytes. After coronary artery ligation in mice, thymosin beta4 treatment resulted in upregulation of ILK and Akt activity in the heart, enhanced early myocyte survival, and improved cardiac function. These findings suggest that thymosin beta4 promotes cardiomyocyte and endothelial migration, survival, and repair and may be a novel therapeutic target in the setting of acute myocardial damage.

Targeted delivery of thymosin beta 4 to the injured myocardium using CREKA-conjugated nanoparticles

“…Cardiac functional parameters were performed via echocardiography as described previously. 5 histochemical and immunohistochemical assessments At 7,14, and 28 days after systemic injection of PBS, Tβ4, NP-Tβ4, or CNP-Tβ4, hearts were harvested and cut into 5-μm cryosections or paraffin-embedded sections. Fibrous tissue was identified by staining sections with an Accustain Trichrome Stains (Masson) kit.…”

“…3,4 Recent studies revealed that Tβ4 increased cardiac function by promoting the survival of cardiomyocytes, [5][6][7] activating resident epicardial progenitor cells, 4,[8][9][10][11][12] and modulating inflammatory responses. 13 Being a peptide, Tβ4 has additional advantages over conventional growth factors because of its small size, high activity, and minimized immunogenicity, 14 and Tβ4 has been regarded as an attractive therapeutic agent for MI clinically (NCT00743769).…”

Vertebrate β‐thymosins: Conserved synteny reveals the relationship between those of bony fish and of land vertebrates

“…b4 has therapeutic potential: as an anti-inflammatory agent [4] and a promoter of wound healing in humans [5] and in relation to acute myocardial damage in a mouse model [6]. b-Thymosins 4, 10 and 15 have shown increased expression associated with malignancy [7][8][9], and the human b15 may provide a valuable diagnostic for malignancy of prostate cancer [10].…”

Interleukin-18-mediated interferon-gamma secretion is regulated by thymosin beta 4 in human NK cells

“…T␤4 could also induce NK cell activation via direct stimulation of the signal machinery or the phosphorylation of transcription factors. It is well known that T␤4 stimulates integrin-linked kinase (ILK) and AKT/Protein Kinase B in cardiomyocyte survival and ERK phosphorylation in paclitaxelinduced cell death and activates plasminogen activator inhibitor-1 (PAI-1) and then induces JAK/STAT cascade (Srivastava et al 2007;Boncela et al 2006;Oh et al 2006). Furthermore, IFN-␥ induction is mediated by the JAK/STAT pathway, which is also involved in actin polymerization (Jacobson et al 1995).…”