The probable role of GPR182 and CALCRL genes in endothelial dysfunction caused by hyperglycemia

Rezaei, Zeynab; Abedi Kichi, Zahra; Behmanesh, Mehrdad

The probable role of GPR182 and CALCRL genes in endothelial dysfunction caused by hyperglycemia

Document Type : Original Research

Authors

zeynab rezaei ¹

zahra abedi kichi ²

Mehrdad Behmanesh ³

¹ MSc, Department of Genetics, Faculty of Biological Science, Tarbiat Modares University, Tehran, Iran.

² PhD student, Department of Genetics, Faculty of Biological Science, Tarbiat Modares University, Tehran, Iran.

³ Professor, Department of Genetics, Faculty of Biological Sciences, Tarbiat Modares University, Tehran, Iran.

Abstract

Abstract: Hyperglycemia is a major cause of diabetes. Hyperglycemia-induced endothelial dysfunction is generally believed to be the basis of diabetic vascular complications such as retinopathy, nephropathy and cardiovascular diseases. The most important molecules in endothelial cells that can sense elevated level of glucose and transmit signals into the cell are G protein-coupled receptors (GPCRs).

In the present study, according to bioinformatics analysis of genomic sequences between healthy and patient individuals, two G proteins GPR182 and CALCRL were selected and their expression level were examined in hyperglycemic and normal conditions in HUVEC as a model of vascular endothelial cells at different glucose concentrations and various time intervals. In addition, the effects of hyperglycemia on cell viability and cell cytotoxicity were assessed by MTT and LDH assay respectively and also morphological changes by immunohistochemistry.

Overall our data reveal a probable role for GPR182 and CALCRL in hyperglycemia-induced endothelial dysfunction. Thus, they could be developed as a potential molecular targets for the endothelial dysfunction therapy.

Keywords

Hyperglycemia

GPCRs

GPR182

CALCRL

Endothelial dysfunction

20.1001.1.23222115.1399.11.2.15.6

Subjects

Molecular biotechnology

1- Alharbi, T., Thomacos, N. and McLelland, G., 2019. Core competencies for diabetes educators: A scoping review. Diabetes & Metabolic Syndrome: Clinical Research & Reviews 13(4), pp. 2671–2682.
2- Reimann, F. and Gribble, F.M., 2016. G protein-coupled receptors as new therapeutic targets for type 2 diabetes. Diabetologia, 59(2), pp.229-233.
3- Dackor, R.T., Fritz-Six, K., Dunworth, W.P., Gibbons, C.L., Smithies, O. and Caron, K.M., 2006. Hydrops fetalis, cardiovascular defects, and embryonic lethality in mice lacking the calcitonin receptor-like receptor gene. Molecular and cellular biology, 26(7), pp.2511-2518.
4- Dai, T., Natarajan, R., Nast, C.C., LaPage, J., Chuang, P., Sim, J., Tong, L., Chamberlin, M., Wang, S. and Adler, S.G., 2006. Glucose and diabetes: effects on podocyte and glomerular p38MAPK, heat shock protein 25, and actin cytoskeleton. Kidney international, 69(5), pp.806-814.
5- Erukainure, O.L., Narainpersad, N., Singh, M., Olakunle, S. and Islam, M.S., 2018. Clerodendrum volubile inhibits key enzymes linked to type 2 diabetes but induces cytotoxicity in human embryonic kidney (HEK293) cells via exacerbated oxidative stress and proinflammation. Biomedicine & Pharmacotherapy, 106, pp.1144-1152.
6- Funk, S.D., Yurdagul, A. and Orr, A.W., 2012. Hyperglycemia and endothelial dysfunction in atherosclerosis: lessons from type 1 diabetes. International journal of vascular medicine, 2012.
7- Habas, K. and Shang, L., 2018. Alterations in intercellular adhesion molecule 1 (ICAM-1) and vascular cell adhesion molecule 1 (VCAM-1) in human endothelial cells. Tissue and Cell, 54, pp.139-143.
8- Harrison, D., Widder, J., Grumbach, I., Chen, W., Weber, M. and Searles, C., 2006. Endothelial mechanotransduction, nitric oxide and vascular inflammation. Journal of internal medicine, 259(4), pp.351-363.
9- Husted, A.S., Trauelsen, M., Rudenko, O., Hjorth, S.A. and Schwartz, T.W., 2017. GPCR-mediated signaling of metabolites. Cell metabolism, 25(4), pp.777-796.
10- Hamledari, H., Sajjadi, S.F., Alikhah, A., Boroumand, M.A. and Behmanesh, M., 2019. ASGR1 but not FOXM1 expression decreases in the peripheral blood mononuclear cells of diabetic atherosclerotic patients. Journal of Diabetes and its Complications, 33(8), pp.539-546.
11- Kim, J.Y., Ku, Y.S., Kim, H.J., Trinh, N.T., Kim, W., Jeong, B., Heo, T.Y., Lee, M.K. and Lee, K.E., 2019. Oral diabetes medication and risk of dementia in elderly patients with type 2 diabetes. Diabetes research and clinical practice, 154, pp.116-123.
12- Liu, C., Wu, J. and Zou, M.H., 2012. Activation of AMP-activated protein kinase alleviates high-glucose-induced dysfunction of brain microvascular endothelial cell tight-junction dynamics. Free Radical Biology and Medicine, 53(6), pp.1213-1221.
13- Weyermann, J., Lochmann, D. and Zimmer, A., 2005. A practical note on the use of cytotoxicity assays. International journal of pharmaceutics, 288(2), pp.369-376.
14- Madonna, R., Geng, Y.J., Shelat, H., Ferdinandy, P. and De Caterina, R., 2014. High glucose-induced hyperosmolarity impacts proliferation, cytoskeleton remodeling and migration of human induced pluripotent stem cells via aquaporin-1. Biochimica et Biophysica Acta (BBA)-Molecular Basis of Disease, 1842(11), pp.2266-2275.
15- Matsumoto, K., Fujishima, K., Moriuchi, A., Saishoji, H. and Ueki, Y., 2010. Soluble adhesion molecule E-selectin predicts cardiovascular events in Japanese patients with type 2 diabetes mellitus. Metabolism, 59(3), pp.320-324.
16- Vitale, C., Mercuro, G., Cornoldi, A., Fini, M., Volterrani, M. and Rosano, G.M.C., 2005. Metformin improves endothelial function in patients with metabolic syndrome. Journal of internal medicine, 258(3), pp.250-256.
17- Nie, Q., Zhu, L., Zhang, L., Leng, B. and Wang, H., 2019. Astragaloside IV protects against hyperglycemia-induced vascular endothelial dysfunction by inhibiting oxidative stress and Calpain-1 activation. Life sciences, 232, p.116662.
18- Pahwa, R., Nallasamy, P. and Jialal, I., 2016. Toll-like receptors 2 and 4 mediate hyperglycemia induced macrovascular aortic endothelial cell inflammation and perturbation of the endothelial glycocalyx. Journal of diabetes and its complications, 30(4), pp.563-572.
19- Pawlak, J.B., Wetzel-Strong, S.E., Dunn, M.K. and Caron, K.M., 2017. Cardiovascular effects of exogenous adrenomedullin and CGRP in Ramp and Calcrl deficient mice. Peptides, 88, pp.1-7.
20- Scholzen, T. and Gerdes, J., 2000. The Ki‐67 protein: from the known and the unknown. Journal of cellular physiology, 182(3), pp.311-322.
21- Hajime, M., Okada, Y., Mori, H., Otsuka, T., Kawaguchi, M., Miyazaki, M., Kuno, F., Sugai, K., Sonoda, S., Tanaka, K. and Kurozumi, A., 2018. Twenty‐four‐hour variations in blood glucose level in Japanese type 2 diabetes patients based on continuous glucose monitoring. Journal of diabetes investigation, 9(1), pp.75-82.
22- Sebastiani, G., Ceccarelli, E., Castagna, M.G. and Dotta, F., 2018. G-protein-coupled receptors (GPCRs) in the treatment of diabetes: Current view and future perspectives. Best Practice & Research Clinical Endocrinology & Metabolism, 32(2), pp.201-213.
23- Wang, H., Yao, Y., Liu, J., Cao, Y., Si, C., Zheng, R., Zeng, C., Guan, H. and Li, L., 2019. Dopamine D4 receptor protected against hyperglycemia-induced endothelial dysfunction via PI3K/eNOS pathway. Biochemical and biophysical research communications, 518(3), pp.554-559.
24- Shukla, K., Sonowal, H., Saxena, A. and Ramana, K.V., 2018. Didymin prevents hyperglycemia-induced human umbilical endothelial cells dysfunction and death. Biochemical pharmacology, 152, pp.1-10.
25- Silambarasan, M., Tan, J., Karolina, D., Armugam, A., Kaur, C. and Jeyaseelan, K., 2016. MicroRNAs in hyperglycemia induced endothelial cell dysfunction. International journal of molecular sciences, 17(4), p.518.
26- Song, K., Han, H.J., Kim, S. and Kwon, J., 2019. Thymosin beta 4 attenuates PrP (106-126)-induced human brain endothelial cells dysfunction. European Journal of Pharmacology, p.172891.
27- Song, K.H., Bae, S.J., Chang, J., Park, J.H., Jo, I., Cho, K.W. and Cho, D.H., 2017. Telmisartan mitigates hyperglycemia-induced vascular inflammation by increasing GSK3β-Ser9 phosphorylation in endothelial cells and mouse aortas. Biochemical and biophysical research communications, 491(4), pp.903-911.