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

Abstract

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.

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

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.

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.