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, Ca2+ influx into endothelial cells can promote ER stress and/or contribute to mechanisms associated to it. In previous work we showed that in human coronary artery endothelial cells (HCAECs) the Ca2+-permeable non-selective cation channel Transient Receptor Potential Canonical 3 (TRPC3) mediates constitutive Ca2+ 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 Ca2+/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 Ca2+ 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.

Functional role of TRP channels in modulating ER stress and Autophagy

“…For example the channels TRPC1[100, 101], TRPV1 [102-109], and TRPC6[110] are expressed at both the ER membrane as well as in the plasma membrane and have been linked to ER Ca 2+ homeostasis. Further, the channels TRPC3 and TRPC6 have each been identified as having a role in ER stress-induced apoptosis [111, 112]. Together it can be acknowledged that TRP channels have a role in maintaining ER Ca 2+ homeostasis and disruption of channel function leads to ER stress.…”

“…Within mouse epithelial cells from pancreatic and parotid acini, the loss of TRPC3 function ameliorates ER stressed induced UPR via PERK signaling [114]. ER stress can cause the activation of Ca 2+ /calmodulin-dependent protein kinase II (CAMKII) and work done in HCAECs has shown Ca 2+ influx by TRPC3 is required for the activation of CAMKII within UPR and the eventual ER-stress induced apoptosis [111, 115, 116]. It has also been shown that canonical transient receptor potential-6 (TRPC6) is expressed in the ER membrane blood platelets [110] and in podocytes and the channel can be activated by albumin [112].…”

TRPC3‐mediated Ca2+ signals as a promising strategy to boost therapeutic angiogenesis in failing hearts: The role of autologous endothelial colony forming cells

“…In this model, advanced atherosclerotic plaques (16 weeks old) displayed larger size and increased macrophage content as compared to non‐transgenic littermates (Smedlund et al, ); moreover, endothelial inflammation was noticeable already in the early lesions only in TRPC3‐overexpressing mice (Smedlund et al, ). Furthermore, constitutive TRPC3‐mediated Ca 2+ influx triggers the unfolded protein response (UPR) in HCAEs and, in doing so, enhances their susceptibility to ER stress‐induced apoptosis (Ampem, Smedlund, & Vazquez, ). This finding is consistent with the notion that many pro‐atherogenic factors promote cause ER stress and consequently activate the UPR in an attempt to restore ER homeostasis (Tabas, ).…”

miR‑454‑3p prevents ox‑LDL‑induced apoptosis in HAECs by targeting TRPC3

“…Apoe knockout mice, a unique mouse model of atherosclerosis, with endothelial-specific overexpression of human TRPC3 exhibited increased size and cellularity of advanced atherosclerotic lesions ( 32 ), supporting a pro-atherogenic role of endothelial TRPC3. Additionally, a previous study reported that TRPC3 is required for EC apoptosis induced by endoplasmic-reticulum stress ( 33 ). Therefore, the present study hypothesized that miR-454-3p may exert its anti-apoptotic effect by suppressing TRPC3.…”