Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2019 Jul;97(7):589-599.
doi: 10.1139/cjpp-2018-0570. Epub 2019 Mar 9.

Tβ4-Ac-SDKP pathway: Any relevance for the cardiovascular system?

Kamal M Kassem  1   2 , Sonal Vaid  1   3 , Hongmei Peng  1 , Sarah Sarkar  1 , Nour-Eddine Rhaleb  1   4
Affiliations
Review

Tβ4-Ac-SDKP pathway: Any relevance for the cardiovascular system?

Kamal M Kassem et al. Can J Physiol Pharmacol. 2019 Jul.

Abstract
in English, French

The last 20 years witnessed the emergence of the thymosin β4 (Tβ4)-N-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP) pathway as a new source of future therapeutic tools to treat cardiovascular and renal diseases. In this review article, we attempted to shed light on the numerous experimental findings pertaining to the many promising cardiovascular therapeutic avenues for Tβ4 and (or) its N-terminal derivative, Ac-SDKP. Specifically, Ac-SDKP is endogenously produced from the 43-amino acid Tβ4 by 2 successive enzymes, meprin α and prolyl oligopeptidase. We also discussed the possible mechanisms involved in the Tβ4-Ac-SDKP-associated cardiovascular biological effects. In infarcted myocardium, Tβ4 and Ac-SDKP facilitate cardiac repair after infarction by promoting endothelial cell migration and myocyte survival. Additionally, Tβ4 and Ac-SDKP have antifibrotic and anti-inflammatory properties in the arteries, heart, lungs, and kidneys, and stimulate both in vitro and in vivo angiogenesis. The effects of Tβ4 can be mediated directly through a putative receptor (Ku80) or via its enzymatically released N-terminal derivative Ac-SDKP. Despite the localization and characterization of Ac-SDKP binding sites in myocardium, more studies are needed to fully identify and clone Ac-SDKP receptors. It remains promising that Ac-SDKP or its degradation-resistant analogs could serve as new therapeutic tools to treat cardiac, vascular, and renal injury and dysfunction to be used alone or in combination with the already established pharmacotherapy for cardiovascular diseases.

Au cours des 20 dernières années, nous avons assisté à l’émergence de la voie de signalisation de la thymosine β4 (Tβ4)– N-acétyl-séryl-aspartyl-lysyl-proline (Ac-SDKP) comme nouvelle source d’outils thérapeutiques futurs pour le traitement de maladies cardiovasculaires et rénales. Dans cet article de synthèse, nous avons tenté de mettre en lumière les nombreux résultats expérimentaux quant aux nombreuses avenues thérapeutiques cardiovasculaires prometteuses pour le Tβ4 ou l’Ac-SDKP, son dérivé N-terminal. Spécifiquement, l’Ac-SDKP est un produit endogène obtenu à partir de Tβ4 de 43 acides aminés par 2 enzymes successives : la méprine et la prolyl oligopeptidase. Nous avons aussi discuté d’éventuels modes d’action pouvant jouer un rôle dans les effets biologiques cardiovasculaires associés au Tβ4–Ac-SDKP. Dans le myocarde infarci, le Tβ4 et l’Ac-SDKP facilitent la réparation du cœur après l’infarctus en favorisant la migration des cellules endothéliales et la survie des myocytes. En outre, le Tβ4 et l’Ac-SDKP ont des propriétés anti-fibrotiques et anti-inflammatoires dans les artères, le cœur, les poumons et les reins, et stimulent l’angiogenèse tant in vitro qu’in vivo. Les effets du Tβ4 peuvent être médiés directement par l’intermédiaire d’un récepteur putatif (Ku80) ou de l’Ac-SDKP, son dérivé N-terminal, libéré de manière enzymatique. En dépit de la localisation et de la caractérisation des sites de liaison de l’Ac-SDKP dans le myocarde, d’autres études seraient nécessaires pour caractériser entièrement et cloner les récepteurs de l’Ac-SDKP. Il demeure prometteur que l’Ac-SDKP ou ses analogues résistants à la dégradation puissent servir de nouveaux outils thérapeutiques contre les lésions et le dysfonctionnement du cœur, des vaisseaux et des reins utilisés seuls ou en association avec des agents pharmacothérapeutiques déjà établis contre les maladies cardiovasculaires. [Traduit par la Rédaction]

Keywords: Ac-SDKP; angiotensin-converting enzyme; cardiovasculaire; cardiovascular; enzyme de conversion de l’angiotensine; renal; rénal; thymosin beta 4; thymosine bêta 4.

PubMed Disclaimer

Conflict of interest statement

Conflict of interest

The authors declare that there is no conflict of interest associated with this work.

Figures

Fig. 1.
Fig. 1.
Amino acid sequence of thymosin β4 (Tβ4) showing the putative meprin-α cleavage sites. Peptides were released after Tβ4 was incubated with recombinant meprin-α and analyzed by a liquid chromatography – mass spectrometer. Meprin-α cleavage sites are marked by solid arrows. Four NH2-terminal intermediate peptides <30 amino acids released from Tβ4 by meprin-α are shown. Prolyl oligopeptidase (POP) active site is indicated by a solid triangle.
Fig. 2.
Fig. 2.
Schematic diagram of sequential hydrolysis of thymosin β4 (Tβ4). In the first step, meprin-α hydrolyzes Tβ4 into NH2-terminal intermediate peptide(s) <30 amino acids. The second step involves prolyl oligopeptidase (POP) hydrolysis of the intermediate peptide(s) that releases N-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP). Tβ4 and Ac-SDKP, via their putative receptors, provide renal and cardiac protection by reducing inflammation and fibrosis and promoting angiogenesis. ACE, angiotensin-converting enzyme.
See this image and copyright information in PMC

References

    1. Anavekar NS, and Solomon SD 2005. Angiotensin II receptor blockade and ventricular remodelling. J. Renin Angiotensin Aldosterone Syst 6(1): 43–48. doi:10.3317/jraas.2005.006. PMID:16088851. - DOI - PubMed
    1. Azizi M, Rousseau A, Ezan E, Guyene TT, Michelet S, Grognet JM, et al. 1996. Acute angiotensin-converting enzyme inhibition increases the plasma level of the natural stem cell regulator N-acetyl-seryl-aspartyl-lysyl-proline. J. Clin. Invest 97(3): 839–844. doi:10.1172/JCI118484. PMID:8609242. - DOI - PMC - PubMed
    1. Azizi M, Ezan E, Nicolet L, Grognet JM, and Ménard J. 1997. High plasma level of N-acetyl-seryl-aspartyl-lysyl-proline: a new marker of chronic angiotensin-converting enzyme inhibition. Hypertension, 30(5): 1015–1019. doi:10.1161/01.HYP.30.5.1015. PMID:9369248. - DOI - PubMed
    1. Banerjee I, Zhang J, Moore-Morris T, Lange S, Shen T, Dalton ND, et al. 2012. Thymosin beta 4 is dispensable for murine cardiac development and function. Circ. Res 110(3): 456–464. doi:10.1161/CIRCRESAHA.111.258616. PMID:22158707. - DOI - PMC - PubMed
    1. Banerjee I, Moore Morris T, Evans SM, and Chen J. 2013. Thymosin beta4 is not required for embryonic viability or vascular development. Circ. Res 112(3): e25–e28. doi:10.1161/CIRCRESAHA.111.300197. PMID:23371905. - DOI - PMC - PubMed

MeSH terms