OBJECTIVE: 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). METHODS AND RESULTS: 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. CONCLUSIONS: 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.
OBJECTIVE: 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). METHODS AND RESULTS: 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. CONCLUSIONS: 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.
Authors: Zachary I Grunewald; Francisco I Ramirez-Perez; Makenzie L Woodford; Mariana Morales-Quinones; Salvador Mejia; Camila Manrique-Acevedo; Ulrich Siebenlist; Luis A Martinez-Lemus; Bysani Chandrasekar; Jaume Padilla Journal: Hypertension Date: 2020-08-24 Impact factor: 10.190
Authors: Gabriela Venturini; Ana I S Moretti; Thaís L S Araujo; Leonardo Y Tanaka; Alexandre Costa Pereira; Francisco R M Laurindo Journal: Cell Stress Chaperones Date: 2019-01-15 Impact factor: 3.667
Authors: Xutong Sun; Manuela Kellner; Ankit A Desai; Ting Wang; Qing Lu; Archana Kangath; Ning Qu; Christina Klinger; Sohrab Fratz; Jason X-J Yuan; Jeffrey R Jacobson; Joe G N Garcia; Ruslan Rafikov; Jeffrey R Fineman; Stephen M Black Journal: Am J Respir Cell Mol Biol Date: 2016-08 Impact factor: 6.914
Authors: Khanh T Do; Geraldine O'Sullivan Coyne; John L Hays; Jeffrey G Supko; Stephen V Liu; Kristin Beebe; Len Neckers; Jane B Trepel; Min-Jung Lee; Tomoko Smyth; Courtney Gannon; Jennifer Hedglin; Alona Muzikansky; Susana Campos; John Lyons; Percy Ivy; James H Doroshow; Alice P Chen; Geoffrey I Shapiro Journal: Cancer Chemother Pharmacol Date: 2020-10-23 Impact factor: 3.333