knk-437 and Ischemia

Heat shock protein 70s (Hsp70s) are molecular chaperones that protect cells from damage in response to various stress stimuli. However, the functions and mechanisms in endothelial cells (ECs) have not been examined. Herein, we investigate the role of Hsp70s, including heat shock cognate protein 70 (Hsc70), which is constitutively expressed in nonstressed cells (ie, ECs).. The Hsp70 inhibitor, KNK437, significantly decreased vascular endothelial growth factor (VEGF)-induced cell migration and tube formation in vitro. KNK437 inhibited the phosphorylation of VEGF-induced Akt and endothelial nitric oxide synthase (eNOS) in human umbilical vein endothelial cells. In a mouse hind limb model of vascular insufficiency, intramuscular inhibition of Hsp70s attenuated collateral and capillary vessel formation. Silencing the Hsc70 gene by short interfering RNA abolished VEGF-induced Akt phosphorylation and VEGF-stimulated human umbilical vein endothelial cell migration and tube formation. As the molecular mechanisms, Hsc70 knockdown reduced the expression of phosphatidylinositol 3-kinase.. Collectively, Hsc70 plays a significant role in ECs via the phosphatidylinositol 3-kinase/Akt pathway. Hsc70 may provide the basis for the development of new therapeutic strategies for angiogenesis.

Topics: Animals; Benzhydryl Compounds; Cell Movement; Cells, Cultured; Disease Models, Animal; Endothelium, Vascular; Hindlimb; HSC70 Heat-Shock Proteins; Humans; Ischemia; Male; Mice; Mice, Inbred C57BL; Neovascularization, Physiologic; Nitric Oxide Synthase Type III; Phosphatidylinositol 3-Kinases; Phosphorylation; Proto-Oncogene Proteins c-akt; Pyrrolidinones; Signal Transduction; Vascular Endothelial Growth Factor A