Centre for Molecular Pharmacology, College of Medical, Veterinary and Life Sciences, University of Glasgow, University Avenue, Glasgow G12 8QQ, UK.
Biochem Soc Trans. 2012 Feb;40(1):210-4. doi: 10.1042/BST20110673.
The small heat-shock protein Hsp20 (heat-shock protein 20), also known as HspB6, has been shown to protect against a number of pathophysiological cardiac processes, including hypertrophy and apoptosis. Following β-adrenergic stimulation and local increases in cAMP, Hsp20 is phosphorylated on Ser16 by PKA (protein kinase A). This covalent modification is required for many of its cardioprotective effects. Both Hsp20 expression levels and its phosphorylation on Ser16 are increased in ischaemic myocardium. Transgenic mouse models with cardiac-specific overexpression of Hsp20 that are subject to ischaemia/reperfusion show smaller myocardial infarcts, and improved recovery of contractile performance during the reperfusion phase, compared with wild-type mice. This has been attributed to Hsp20's ability to protect against cardiomyocyte necrosis and apoptosis. Phosphomimics of Hsp20 (S16D mutants) confer improved protection from β-agonist-induced apoptosis in the heart, whereas phospho-null mutants (S16A) provide no protection. Naturally occurring mutants of Hsp20 at position 20 (P20L substitution) are associated with markedly reduced Hsp20 phosphorylation at Ser16, and this lack of phosphorylation correlates with abrogation of Hsp20's cardioprotective effects. Therefore phosphorylation of Hsp20 at Ser16 by PKA is vital for the cardioprotective actions of this small heat-shock protein. Selective targeting of signalling elements that can enhance this modification represents an exciting new therapeutic avenue for the prevention and treatment of myocardial remodelling and ischaemic injury.
小分子热休克蛋白 Hsp20（热休克蛋白 20），也称为 HspB6，已被证明可预防多种病理生理心脏过程，包括肥大和细胞凋亡。在β-肾上腺素能刺激和局部 cAMP 增加后，Hsp20 被蛋白激酶 A（PKA）磷酸化 Ser16。这种共价修饰是其许多心脏保护作用所必需的。缺血心肌中 Hsp20 的表达水平及其 Ser16 上的磷酸化均增加。在缺血/再灌注的心脏中，过表达 Hsp20 的心脏特异性转基因小鼠模型显示出较小的心肌梗死，并且在再灌注期间收缩性能的恢复得到改善，与野生型小鼠相比。这归因于 Hsp20 防止心肌细胞坏死和细胞凋亡的能力。Hsp20 的磷酸模拟物（S16D 突变体）可提供改善的保护，防止β-激动剂诱导的心脏细胞凋亡，而磷酸化缺失突变体（S16A）则无保护作用。Hsp20 位置 20 的天然突变体（P20L 取代）与 Ser16 处的 Hsp20 磷酸化明显降低相关，这种缺乏磷酸化与 Hsp20 的心脏保护作用的消除相关。因此，PKA 对 Hsp20 的 Ser16 磷酸化对这种小分子热休克蛋白的心脏保护作用至关重要。针对可以增强这种修饰的信号转导元件的选择性靶向代表了预防和治疗心肌重塑和缺血损伤的令人兴奋的新治疗途径。
