title: Pharmacological evidence for a role of the transient receptor potential canonical 3 (TRPC3) channel in endoplasmic reticulum stress-induced apoptosis of human coronary artery endothelial cells.
abstract: Unresolved endoplasmic reticulum (ER) stress, with the subsequent persistent activation of the unfolded protein response (UPR) is a well-recognized mechanism of endothelial cell apoptosis with a major impact on the integrity of the endothelium during the course of cardiovascular diseases. As in other cell types, Ca(2+) influx into endothelial cells can promote ER stress and/or contribute to mechanisms associated with it. In previous work we showed that in human coronary artery endothelial cells (HCAECs) the Ca(2+)-permeable non-selective cation channel Transient Receptor Potential Canonical 3 (TRPC3) mediates constitutive Ca(2+) influx which is critical for operation of inflammatory signaling in these cells, through a mechanism that entails coupling of TRPC3 constitutive function to activation of Ca(2+)/calmodulin-dependent protein kinase II (CAMKII). TRPC3 has been linked to UPR signaling and apoptosis in cells other than endothelial, and CAMKII is a mediator of ER stress-induced apoptosis in various cell types, including endothelial cells. In the present work we used a pharmacological approach to examine whether in HCAECs TRPC3 and CAMKII also contribute to mechanisms of ER stress-induced apoptosis. The findings show for the first time that in HCAECs activation of the UPR and the subsequent ER stress-induced apoptosis exhibit a strong requirement for constitutive Ca(2+) influx and that TRPC3 contributes to this process. In addition, we obtained evidence indicating that, similar to its roles in non-endothelial cells, CAMKII participates in ER stress-induced apoptosis in HCAECs.
authors.affiliation: Department of Physiology and Pharmacology, University of Toledo College of Medicine and Life Sciences, Health Science Campus, 3000 Transverse Dr., Toledo, OH 43614, USA.
authors.forename: Prince T
authors.initials: PT
authors.lastname: Ampem
authors.affiliation: Department of Physiology and Pharmacology, University of Toledo College of Medicine and Life Sciences, Health Science Campus, 3000 Transverse Dr., Toledo, OH 43614, USA.
authors.forename: Kathryn
authors.initials: K
authors.lastname: Smedlund
authors.affiliation: Department of Physiology and Pharmacology, University of Toledo College of Medicine and Life Sciences, Health Science Campus, 3000 Transverse Dr., Toledo, OH 43614, USA; Center for Diabetes and Endocrine Research, Center for Hypertension and Personalized Medicine, University of Toledo College of Medicine and Life Sciences, Health Science Campus, 3000 Transverse Dr., Toledo, OH 43614, USA. Electronic address: Guillermo.Vazquez@utoledo.edu.
authors.forename: Guillermo
authors.initials: G
authors.lastname: Vazquez
mesh_terms: D017209:Apoptosis / Q000502:physiology*; D002118:Calcium / Q000378:metabolism; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000378:metabolism; D002460:Cell Line; D003331:Coronary Vessels / Q000378:metabolism*; D004721:Endoplasmic Reticulum / Q000378:metabolism; D059865:Endoplasmic Reticulum Stress / Q000502:physiology*; D042783:Endothelial Cells / Q000378:metabolism*; D004727:Endothelium / Q000378:metabolism; D006801:Humans; D015398:Signal Transduction / Q000502:physiology; D050052:TRPC Cation Channels / Q000378:metabolism*
chemical_list: D050052:TRPC Cation Channels; C104603:TRPC3 cation channel; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D002118:Calcium
keywords: Endoplasmic reticulum stress; Endothelial cell apoptosis; TRPC3 channels