Vivek Krishna Pulakazhi Venu1,2, Mahmoud Saifeddine1, Koichiro Mihara1, Mahmoud El-Daly1,3, Darrell Belke2, Jonathan L E Dean4, Edward R O'Brien2, Simon A Hirota1, Morley D Hollenberg1,5. 1. Department of Physiology and Pharmacology, Inflammation Research Network-Snyder Institute for Chronic Disease, University of Calgary Cumming School of Medicine, Calgary, AB, Canada. 2. Department of Cardiac Sciences, Libin Cardiovascular Institute of Alberta, University of Calgary Cumming School of Medicine, Calgary, AB, Canada. 3. Department of Pharmacology and Toxicology, Faculty of Pharmacy, Minia University, El-Minia, Egypt. 4. Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, UK. 5. Department of Medicine, University of Calgary Cumming School of Medicine, Calgary, AB, Canada.
Abstract
BACKGROUND AND PURPOSE: Previously, we demonstrated that exogenous heat shock protein 27 (HSP27/gene, HSPB1) treatment of human endothelial progenitor cells (EPCs) increases the synthesis and secretion of VEGF, improves EPC-migration/re-endothelialization and decreases neo-intima formation, suggesting a role for HSPB1 in regulating EPC function. We hypothesized that HSPB1 also affects mature endothelial cells (ECs) to alter EC-mediated vasoreactivity in vivo. Our work focused on endothelial NOS (eNOS)/NO-dependent relaxation induced by ACh and the coagulation pathway-activated receptor, proteinase-activated receptor 2 (PAR2). EXPERIMENTAL APPROACH: Aorta rings from male and female wild-type, HSPB1-null and HSPB1 overexpressing (HSPB1o/e) mice were contracted with phenylephrine, and NOS-dependent relaxation responses to ACh and PAR2 agonist, 2-furoyl-LIGRLO-NH2 , were measured without and with L-NAME and ODQ, either alone or in combination to block NO synthesis/action. Tissues from female HSPB1-null mice were treated in vitro with recombinant HSP27 and then used for bioassay as above. Furthermore, oestrogen-specific effects were evaluated using a bioassay of aorta isolated from ovariectomized mice. KEY RESULTS: Relative to males, HSPB1-null female mice exhibited an increased L-NAME-resistant relaxation induced by activation of either PAR2 or muscarinic ACh receptors that was blocked in the concurrent presence of both L-NAME and ODQ. mRNAs (qPCR) for eNOS and ODQ-sensitive guanylyl-cyclase were increased in females versus males. Treatment of isolated aorta tissue with HSPB1 improved tissue responsiveness in the presence of L-NAME. Ovariectomy did not affect NO sensitivity, supporting an oestrogen-independent role for HSPB1. CONCLUSIONS AND IMPLICATIONS: HSPB1 can regulate intact vascular endothelial function to affect NO-mediated vascular relaxation, especially in females.
BACKGROUND AND PURPOSE: Previously, we demonstrated that exogenous heat shock protein 27 (HSP27/gene, HSPB1) treatment of human endothelial progenitor cells (EPCs) increases the synthesis and secretion of VEGF, improves EPC-migration/re-endothelialization and decreases neo-intima formation, suggesting a role for HSPB1 in regulating EPC function. We hypothesized that HSPB1 also affects mature endothelial cells (ECs) to alter EC-mediated vasoreactivity in vivo. Our work focused on endothelial NOS (eNOS)/NO-dependent relaxation induced by ACh and the coagulation pathway-activated receptor, proteinase-activated receptor 2 (PAR2). EXPERIMENTAL APPROACH: Aorta rings from male and female wild-type, HSPB1-null and HSPB1 overexpressing (HSPB1o/e) mice were contracted with phenylephrine, and NOS-dependent relaxation responses to ACh and PAR2 agonist, 2-furoyl-LIGRLO-NH2 , were measured without and with L-NAME and ODQ, either alone or in combination to block NO synthesis/action. Tissues from female HSPB1-null mice were treated in vitro with recombinant HSP27 and then used for bioassay as above. Furthermore, oestrogen-specific effects were evaluated using a bioassay of aorta isolated from ovariectomized mice. KEY RESULTS: Relative to males, HSPB1-null female mice exhibited an increased L-NAME-resistant relaxation induced by activation of either PAR2 or muscarinic ACh receptors that was blocked in the concurrent presence of both L-NAME and ODQ. mRNAs (qPCR) for eNOS and ODQ-sensitive guanylyl-cyclase were increased in females versus males. Treatment of isolated aorta tissue with HSPB1 improved tissue responsiveness in the presence of L-NAME. Ovariectomy did not affect NO sensitivity, supporting an oestrogen-independent role for HSPB1. CONCLUSIONS AND IMPLICATIONS: HSPB1 can regulate intact vascular endothelial function to affect NO-mediated vascular relaxation, especially in females.
Authors: Tara A Seibert; Benjamin Hibbert; Yong-Xiang Chen; Katey Rayner; Trevor Simard; Tieqiang Hu; Charles M Cuerrier; Xiaoling Zhao; Jacqueline de Belleroche; Benjamin J W Chow; Steven Hawken; Kumanan R Wilson; Edward R O'Brien Journal: J Am Coll Cardiol Date: 2013-06-10 Impact factor: 24.094
Authors: Vivek Krishna Pulakazhi Venu; Mahmoud Saifeddine; Koichiro Mihara; Mahmoud El-Daly; Darrell Belke; Jonathan L E Dean; Edward R O'Brien; Simon A Hirota; Morley D Hollenberg Journal: Br J Pharmacol Date: 2018-04-25 Impact factor: 8.739
Authors: Cara C Rada; Hilda Mejia-Pena; Neil J Grimsey; Isabel Canto Cordova; Joshua Olson; Jacob M Wozniak; David J Gonzalez; Victor Nizet; JoAnn Trejo Journal: Sci Signal Date: 2021-08-31 Impact factor: 8.192