Ampem Prince T, Smedlund Kathryn, Vazquez Guillermo
Department of Physiology and Pharmacology, University of Toledo College of Medicine and Life Sciences, Health Science Campus, 3000 Transverse Dr., Toledo, OH 43614, USA.
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.
Vascul Pharmacol. 2016 Jan;76:42-52. doi: 10.1016/j.vph.2015.07.011. Epub 2015 Jul 26.
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.
未解决的内质网（ER）应激以及随之而来的未折叠蛋白反应（UPR）的持续激活，是一种公认的内皮细胞凋亡机制，在心血管疾病过程中对内皮的完整性有重大影响。与其他细胞类型一样，Ca(2+)流入内皮细胞可促进ER应激和/或促成与之相关的机制。在先前的工作中，我们表明，在人冠状动脉内皮细胞（HCAECs）中，Ca(2+)通透的非选择性阳离子通道瞬时受体电位经典型3（TRPC3）介导组成性Ca(2+)流入，这对于这些细胞中炎症信号的运作至关重要，其机制是将TRPC3的组成性功能与Ca(2+)/钙调蛋白依赖性蛋白激酶II（CAMKII）的激活相偶联。TRPC3已与内皮细胞以外的细胞中的UPR信号传导和凋亡相关联，并且CAMKII是包括内皮细胞在内的各种细胞类型中ER应激诱导的凋亡的介质。在本研究中，我们采用药理学方法来研究在HCAECs中TRPC3和CAMKII是否也促成ER应激诱导的凋亡机制。研究结果首次表明，在HCAECs中，UPR的激活以及随后的ER应激诱导的凋亡对组成性Ca(2+)流入有强烈需求，并且TRPC3促成了这一过程。此外，我们获得的证据表明，与它在非内皮细胞中的作用类似，CAMKII参与了HCAECs中ER应激诱导的凋亡。
