title: C-terminal variable AGES domain of Thymosin β4: the molecule's primary contribution in support of post-ischemic cardiac function and repair.
abstract: Repairing defective cardiac cells is important towards improving heart function. Due to the frequency and severity of ischemic heart disease, management of patients featuring this type of cardiac failure receives significant interest. Previously we discovered that Thymosin β4 (TB4), a 43 amino-acid secreted actin sequestering peptide, is beneficial for myocardial cell survival and coronary re-growth after infarction in adult mammals. Considering the regenerative potential of full-length TB4 in the heart, and that minimal structural variations alter TB4's influence on actin assembly and cell movement, we investigated how various TB4 domains affect cardiac cell behavior and post-ischemic mammalian heart function. We synthesized 17 domain combinations of full-length TB4 and analyzed their impact on embryonic cardiac cells in vitro, and after cardiac infarction in vivo. We discovered the domains of TB4 affect cardiac cell behavior distinctly. We revealed TB4 specific C-terminal tetrapeptide, AGES, increases embryonic cardiac cell migration and myocyte beating in culture, and improves adult mammalian heart function following ischemia. Investigating the molecular background and mechanism we discovered systemic injection of AGES enhances early myocyte survival by activating Akt-mediated signaling mechanisms, increases coronary vessel growth and inhibits inflammation in mice and pigs. Biodistribution analyses revealed cardiomyocytes uptake AGES efficiently in vitro and in vivo projecting a potential independent clinical utilization for the tetrapeptide. Our comprehensive domain investigations also suggest, preservation and/or restoration of cardiomyocyte communication is a target of TB4 and AGES, and critical to improve post-ischemic heart function in pigs. In summary, we identified the C-terminal four amino-acid variable end of TB4 as the essential and responsible domain for the molecule's full benefits in the hypoxic heart. Additionally, we introduced AGES as a novel, systemically applicable drug candidate to aid cardiac infarction in adult mammals.
authors.affiliation: Internal Medicine I, University Clinic Grosshadern, Munich 81377, Germany.
authors.forename: Rabea
authors.initials: R
authors.lastname: Hinkel
authors.affiliation: Protein Chemistry Technology Center University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Haydn L
authors.initials: HL
authors.lastname: Ball
authors.affiliation: Department of Cardiovascular and Thoracic Surgery University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: J Michael
authors.initials: JM
authors.lastname: DiMaio
authors.affiliation: Department of Cardiovascular and Thoracic Surgery University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Santwana
authors.initials: S
authors.lastname: Shrivastava
authors.affiliation: Department of Cardiovascular and Thoracic Surgery University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Jeffrey E
authors.initials: JE
authors.lastname: Thatcher
authors.affiliation: Advanced Imaging Research Center, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Ajay N
authors.initials: AN
authors.lastname: Singh
authors.affiliation: Advanced Imaging Research Center, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Xiankai
authors.initials: X
authors.lastname: Sun
authors.affiliation: University of Pecs, Faculty of Medicine, Szentagothai Research Centre, Pecs 7624, Hungary.
authors.forename: Gabor
authors.initials: G
authors.lastname: Faskerti
authors.affiliation: Department of Molecular Biology University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Eric N
authors.initials: EN
authors.lastname: Olson
authors.affiliation: Internal Medicine I, University Clinic Grosshadern, Munich 81377, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Kupatt
authors.affiliation: Department of Cardiovascular and Thoracic Surgery University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; University of Pecs, Faculty of Medicine, Szentagothai Research Centre, Pecs 7624, Hungary. Electronic address: ibockm@gmail.com.
authors.forename: Ildiko
authors.initials: I
authors.lastname: Bock-Marquette
mesh_terms: D020816:Amino Acid Motifs / Q000235:genetics; D000818:Animals; D049109:Cell Proliferation / Q000235:genetics; D002470:Cell Survival / Q000235:genetics; D003331:Coronary Vessels / Q000187:drug effects / Q000254:growth & development; D018507:Gene Expression Regulation, Developmental; D006801:Humans; D051379:Mice; D009203:Myocardial Infarction / Q000196:embryology / Q000235:genetics* / Q000473:pathology; D017202:Myocardial Ischemia / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000473:pathology; D010455:Peptides / Q000008:administration & dosage; D013552:Swine; D013947:Thymosin / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D000099201:Thymosin beta(4)
chemical_list: D010455:Peptides; D013947:Thymosin; D000099201:Thymosin beta(4)
keywords: Connexins; Drug research; Infarct remodeling; Myocardial infarction; Thymosin beta-4