a Hypertension and Vascular Research Division, Department of Internal Medicine, Henry Ford Hospital, Detroit, MI 48202, USA.
b Internal Medicine Department, University of Cincinnati Medical Center, Cincinnati, OH 45219, USA.
Can J Physiol Pharmacol. 2019 Jul;97(7):589-599. doi: 10.1139/cjpp-2018-0570. Epub 2019 Mar 9.
The last 20 years witnessed the emergence of the thymosin β4 (Tβ4)--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.
过去 20 年见证了胸腺素β4（Tβ4）-乙酰丝氨酰-天冬氨酰-赖氨酰-脯氨酸（Ac-SDKP）途径的出现，成为治疗心血管和肾脏疾病的未来治疗工具的新来源。在这篇综述文章中，我们试图阐明与 Tβ4 和（或）其 N 端衍生物 Ac-SDKP 许多有前途的心血管治疗途径相关的许多实验发现。具体而言，Ac-SDKP 是由 2 种连续的酶，即金属蛋白酶α和脯氨酸寡肽酶，从 43 个氨基酸的 Tβ4 内源性产生的。我们还讨论了 Tβ4-Ac-SDKP 相关心血管生物学效应涉及的可能机制。在梗死心肌中，Tβ4 和 Ac-SDKP 通过促进内皮细胞迁移和心肌细胞存活来促进梗死后的心脏修复。此外，Tβ4 和 Ac-SDKP 在动脉、心脏、肺和肾脏中具有抗纤维化和抗炎作用，并刺激体外和体内血管生成。Tβ4 的作用可以通过假定的受体（Ku80）直接介导，也可以通过其酶促释放的 N 端衍生物 Ac-SDKP 介导。尽管在心肌中定位和表征了 Ac-SDKP 结合位点，但仍需要更多的研究来充分鉴定和克隆 Ac-SDKP 受体。Ac-SDKP 或其抗降解类似物有望成为治疗心脏、血管和肾脏损伤和功能障碍的新治疗工具，可单独使用或与已建立的心血管疾病药物治疗联合使用，这仍然很有前景。
