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PRINCE DISSERTATION final upload 1.pdf (3.68 MB)

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The Transient Receptor Potential Canonical 3 (TRPC3) Channel: Novel Role in Endothelial Cell Apoptosis and its Impact on Atherosclerosis

Ampem, Prince Tuffour
http://orcid.org/0000-0002-3484-3853
http://rave.ohiolink.edu/etdc/view?acc_num=mco1493230041479167

Abstract Details

2017, Doctor of Philosophy (PhD), University of Toledo, Biomedical Sciences (Molecular Medicine).
Atherosclerosis is the main cause of coronary heart disease, the leading cause of mortality in developed countries. Development of atherosclerotic lesions is in part, associated with increased apoptosis of endothelial cells and disturbance of endothelial integrity. By virtue of its important role and strategic anatomic location in the arterial tree, the endothelium plays a major role in all phases of lesion development. In endothelial cells, a number of atherorelevant systemic and local factors induce endoplasmic reticulum (ER) stress by causing disturbance in endothelial cell ER homeostasis which activates the unfolded protein response (UPR). Although this concerted and adaptive process is initially aimed at protecting the cell, sustained and unresolved ER stress can lead to endothelial cell apoptosis. In a number of cell types, persistent and/or exacerbated Ca2+ influx has also been shown to promote ER stress. In previous studies from our laboratory it was shown that in human coronary artery endothelial cells (HCAECs) constitutive Ca2+ influx plays a critical role in inflammatory signaling, and that the Transient Receptor Potential Canonical 3 (TRPC3) channel mediates such constitutive Ca2+ entry, which is exacerbated under atherorelevant conditions. It was also observed in these studies that TRPC3 constitutive function couples to Ca2+/calmodulin-dependent protein kinase II (CAMKII) to drive inflammatory signaling. In other cell types, TRPC3 has been found to contribute to UPR signaling and apoptosis, and CAMKII is shown to act as a mediator in the signaling pathway that results in ER stress-mediated apoptotic cell death. However, whether a similar role of TRPC3 exists in HCAECs remained unknown. In this work, we first examined whether inhibition of constitutive Ca2+ influx in general and TRPC3 in particular, plays a role in ER stress-induced apoptosis in HCAECs. Our results show that global blockade of constitutive Ca2+ influx or buffering of intracellular Ca2+ changes, markedly decreased the susceptibility of HCAECs to ER stress-induced apoptosis. Notably, we found that selective inhibition of TRPC3 resulted in decreased UPR activation and reduced susceptibility of HCAECs to ER stress-induced apoptosis. Our findings provide pharmacological evidence suggesting that TRPC3, through its constitutive function, supports mechanisms of ER stress-induced apoptosis in an atherorelevant cell type. In order to examine if and to what extent this action of TRPC3 is of relevance to atherosclerotic lesion development and endothelial cell apoptosis in vivo, we used a transgenic mouse model with endothelial specific gain of TRPC3 function. Compared with non-transgenic control mice, atherosclerotic lesions of transgenic mice had significantly increased plaque size and macrophage content, and notably increased endothelial cell apoptosis. These studies show for the first time, a role of TRPC3 in endothelial apoptosis in the context of atherosclerosis and suggest that this pro-apoptotic role contributes to the pro-atherogenic effect of endothelial TRPC3.
Guillermo Vazquez, Ph.D. (Committee Chair)
Bina Joe, Ph.D. (Committee Member)
David Giovannucci, Ph.D. (Committee Member)
Viviana Ferreira, Ph.D. (Committee Member)
Sivarajan Kumarasamy, Ph.D. (Committee Member)
128 p.
Biomedical Research
TRPC3; ER stress; Unfolded protein response; apoptosis; Endothelial cells; Atherosclerosis; Calcium influx; CAMKII; STAT1; JNK; Coronary artery disease; lesion; Thapsigargin; Tunicamycin; Pyr10; Apoe knockout; transgenic mouse

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Citations

  • Ampem, P. T. (2017). The Transient Receptor Potential Canonical 3 (TRPC3) Channel: Novel Role in Endothelial Cell Apoptosis and its Impact on Atherosclerosis [Doctoral dissertation, University of Toledo]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=mco1493230041479167

    APA Style (7th edition)

  • Ampem, Prince. The Transient Receptor Potential Canonical 3 (TRPC3) Channel: Novel Role in Endothelial Cell Apoptosis and its Impact on Atherosclerosis. 2017. University of Toledo, Doctoral dissertation. OhioLINK Electronic Theses and Dissertations Center, http://rave.ohiolink.edu/etdc/view?acc_num=mco1493230041479167.

    MLA Style (8th edition)

  • Ampem, Prince. "The Transient Receptor Potential Canonical 3 (TRPC3) Channel: Novel Role in Endothelial Cell Apoptosis and its Impact on Atherosclerosis." Doctoral dissertation, University of Toledo, 2017. http://rave.ohiolink.edu/etdc/view?acc_num=mco1493230041479167

    Chicago Manual of Style (17th edition)

mco1493230041479167
275
© 2017, all rights reserved.
This open access ETD is published by University of Toledo Health Science Campus and OhioLINK.