Guangdong Medical University, Guangdong Dongguan, 523808, China.
Model Animal Research Center, Nanjing University, Jiangsu Nanjing, 210028, China.
J Cardiovasc Transl Res. 2023 Oct;16(5):1220-1231. doi: 10.1007/s12265-023-10380-y. Epub 2023 Mar 29.
Phosphoinositide-dependent protein kinase-1 (PDK), a master kinase and involved in multiple signaling transduction, participates in regulating embryonic cardiac development and postnatal cardiac remodeling. Germline PDK knockout mice displayed no heart development; in this article, we deleted PDK in heart tissue with different cre to characterize the temporospatial features and find the relevance with congenital heart disease(CHD), furthermore to investigate the underlying mechanism. Knocking out PDK with Nkx2.5-cre, the heart showed prominent pulmonic stenosis. Ablated PDK with Mef2c-cre, the second heart field (SHF) exhibited severe hypoplasia. And deleted PDK with αMHC-cre, the mice displayed dilated heart disease, protein analysis indicated PI3K and ERK were activated; meanwhile, PDK-AKT-GSK3, and S6K-S6 were disrupted; phosphorylation level of Akt, S6k, and Gsk3 enhanced; however, Akt, S6k, and Gsk3 decreased. In mechanism investigation, we found SHP membrane localization and phosphorylation level of SHP2 elevated, which suggested SHP likely mediated the disruption.
磷酸肌醇依赖蛋白激酶-1（PDK）是一种主要的激酶，参与多种信号转导，参与调节胚胎心脏发育和出生后心脏重塑。PDK 基因敲除小鼠没有心脏发育；在本文中，我们使用不同的 cre 基因在心脏组织中敲除 PDK，以描述其时空特征，并发现与先天性心脏病（CHD）的相关性，进一步探讨其潜在机制。使用 Nkx2.5-cre 敲除 PDK，心脏表现出明显的肺动脉瓣狭窄。使用 Mef2c-cre 敲除 PDK，第二心区（SHF）严重发育不良。使用αMHC-cre 敲除 PDK，小鼠表现出扩张型心脏病，蛋白分析表明 PI3K 和 ERK 被激活；同时，PDK-AKT-GSK3 和 S6K-S6 被破坏；Akt、S6k 和 Gsk3 的磷酸化水平增强，而 Akt、S6k 和 Gsk3 减少。在机制研究中，我们发现 SHP 的膜定位和 SHP2 的磷酸化水平升高，提示 SHP 可能介导了这种破坏。
