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The phosphorylation of CHK1 at Ser345 regulates the phenotypic switching of vascular smooth muscle cells both in vitro and in vivo

Background and aims: DNA damage and repair have been shown to be associated with carotid artery restenosis and atherosclerosis. The proliferation and migration of vascular smooth muscle cells (VSMCs) is the main cause of artery stenosis. This study aims to define the relationship between DNA damage and VSMCs proliferation.

Methods: A rat carotid artery injury model was established, and human and rat VSMCs cultured in vitro. H2O2 was used to induce DNA damage in vitro. The selected CHK1 inhibitor, LY2603618, was used to inhibit CHK1 phosphorylation both in vivo and in vitro. γH2AX, αSMA and phosphorylated CHK1 were detected both in rat carotid artery and cultured VSMCs from different groups. Hyperplasia ratio of rat carotid artery intimal was measured.

Results: DNA double-strand breaks occur in the rat carotid artery after injury. DNA damage induces CHK1 phosphorylation and down-regulates αSMA expression in VSMCs both in vitro and in vivo. The inhibition of CHK1 phosphorylation rescues αSMA expression in VSMCs both in vitro and in vivo, and rat carotid intimal hyperplasia after injury was suppressed.

Conclusions: Our data demonstrated that phosphorylation of CHK1 under DNA damage stress modulates VSMCs phenotypic switching. CHK1 inhibition may be a potential therapeutic strategy for intima hyperplasia treatment.

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S2626 Rabusertib (LY2603618) Rabusertib (LY2603618, IC-83) is a highly selective Chk1 inhibitor with potential anti-tumor activity in a cell-free assay. IC50=7 nM, showing approximately 100-fold more potent against Chk1 than against any of the other protein kinases evaluated. Rabusertib (LY2603618) induces cell cycle arrest, DNA damage response and autophagy in cancer cells. Rabusertib (LY2603618) induces bak-dependent apoptosis in AML cell lines. (62) (7)

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