Int J Biol Sci 2017; 13(9):1203-1212. doi:10.7150/ijbs.19666 This issue Cite

Research Paper

ATP2B1 gene Silencing Increases Insulin Sensitivity through Facilitating Akt Activation via the Ca2+/calmodulin Signaling Pathway and Ca2+-associated eNOS Activation in Endothelial Cells

Yang Long1, 2, Ji-yi Xia3, Shao-wei Chen4, Chen-lin Gao1, Guan-nan Liang2, Xue-mei He2, Jian Wu2, Chun-xia Jiang1, Xin Liu2, Wei Huang1, Qin Wan1✉, Yong Xu1, 3✉

1. Department of Endocrinology, The Affiliated Hospital of Southwest Medical University, Luzhou, 646000, Sichuan, P R China;
2. Laboratory of Endocrinology, Experimental Medicine Center, The Affiliated Hospital of Southwest Medical University, Luzhou, 646000, Sichuan, P R China;
3. Key Laboratory of Medical Electrophysiology of Ministry of Education, Collaborative Innovation Center for Prevention and Treatment of Cardiovascular Disease, Institute of Cardiovascular Research, Southwest Medical University, Luzhou, 646000, Sichuan, P R China;
4. Medical Reproduction Center, The Affiliated Hospital of Southwest Medical University, Luzhou, 646000, Sichuan, P R China.

Citation:
Long Y, Xia Jy, Chen Sw, Gao Cl, Liang Gn, He Xm, Wu J, Jiang Cx, Liu X, Huang W, Wan Q, Xu Y. ATP2B1 gene Silencing Increases Insulin Sensitivity through Facilitating Akt Activation via the Ca2+/calmodulin Signaling Pathway and Ca2+-associated eNOS Activation in Endothelial Cells. Int J Biol Sci 2017; 13(9):1203-1212. doi:10.7150/ijbs.19666. https://www.ijbs.com/v13p1203.htm
Other styles

File import instruction

Abstract

Graphic abstract

Endothelial cell insulin resistance may be partially responsible for the higher risk of atherosclerosis and cardiovascular disease in populations with insulin resistance and type 2 diabetes mellitus (T2DM). A genome-wide association study revealed a significant association between the ATPase plasma membrane Ca2+ transporting 1 (ATP2B1) gene and T2DM in two community-based cohorts from the Korea Association Resource Project. However, little is known about the implication of the ATP2B1 gene on T2DM. In the present study, we investigated the role of the ATP2B1 gene in endothelial cell insulin sensitivity. ATP2B1 gene silencing resulted in enhanced intracellular calcium concentrations and increased insulin-induced Akt activation compared to that in the negative siRNA-transfected HUVECs (Human Umbilical Vein Endothelial Cells). The elevated insulin sensitivity mediated by ATP2B1 gene silencing was Ca2+/calmodulin-dependent, as verified by administration of the calcium chelator BAPTA-AM or the calmodulin-specific antagonist W7. Moreover, higher levels of phosphorylation of eNOS (Ser1177) were observed in ATP2B1-silenced HUVECs. In addition to BAPTA-AM and W7, L-NAME, an eNOS antagonist, abolished insulin-induced Akt phosphorylation at Ser473 in both si-Neg and si-ATP2B1-transfected endothelial cells. These results indicate that the enhanced insulin sensitivity in ATP2B1-silenced endothelial cells is alternatively dependent on an increase in intracellular Ca2+ and the subsequent activation of the Ca2+/calmodulin/eNOS/Akt signaling pathway. In summary, ATP2B1 gene silencing increased insulin sensitivity in endothelial cells by directly modulating the Ca2+/calmodulin signaling pathway and via the Ca2+/calmodulin/eNOS/Akt signaling pathway alternatively.

Keywords: ATPase plasma membrane Ca2+ transporting 1, Plasma Membrane Calcium ATPase 1, Endothelial Insulin Resistance, Calcium, Calmodulin.


Citation styles

APA
Long, Y., Xia, J.y., Chen, S.w., Gao, C.l., Liang, G.n., He, X.m., Wu, J., Jiang, C.x., Liu, X., Huang, W., Wan, Q., Xu, Y. (2017). ATP2B1 gene Silencing Increases Insulin Sensitivity through Facilitating Akt Activation via the Ca2+/calmodulin Signaling Pathway and Ca2+-associated eNOS Activation in Endothelial Cells. International Journal of Biological Sciences, 13(9), 1203-1212. https://doi.org/10.7150/ijbs.19666.

ACS
Long, Y.; Xia, J.y.; Chen, S.w.; Gao, C.l.; Liang, G.n.; He, X.m.; Wu, J.; Jiang, C.x.; Liu, X.; Huang, W.; Wan, Q.; Xu, Y. ATP2B1 gene Silencing Increases Insulin Sensitivity through Facilitating Akt Activation via the Ca2+/calmodulin Signaling Pathway and Ca2+-associated eNOS Activation in Endothelial Cells. Int. J. Biol. Sci. 2017, 13 (9), 1203-1212. DOI: 10.7150/ijbs.19666.

NLM
Long Y, Xia Jy, Chen Sw, Gao Cl, Liang Gn, He Xm, Wu J, Jiang Cx, Liu X, Huang W, Wan Q, Xu Y. ATP2B1 gene Silencing Increases Insulin Sensitivity through Facilitating Akt Activation via the Ca2+/calmodulin Signaling Pathway and Ca2+-associated eNOS Activation in Endothelial Cells. Int J Biol Sci 2017; 13(9):1203-1212. doi:10.7150/ijbs.19666. https://www.ijbs.com/v13p1203.htm

CSE
Long Y, Xia Jy, Chen Sw, Gao Cl, Liang Gn, He Xm, Wu J, Jiang Cx, Liu X, Huang W, Wan Q, Xu Y. 2017. ATP2B1 gene Silencing Increases Insulin Sensitivity through Facilitating Akt Activation via the Ca2+/calmodulin Signaling Pathway and Ca2+-associated eNOS Activation in Endothelial Cells. Int J Biol Sci. 13(9):1203-1212.

This is an open access article distributed under the terms of the Creative Commons Attribution (CC BY-NC) license (https://creativecommons.org/licenses/by-nc/4.0/). See http://ivyspring.com/terms for full terms and conditions.
Popup Image