Activation of GPR81 lactate receptors stimulates mitochondrial biogenesis in cerebral microvessel endothelial cells
- Authors: Khilazheva E.D.1, Pisareva N.V.1, Morgun A.V.1, Boitsova E.B.1, Taranushenko T.E.1, Frolova O.V.1, Salmina A.B.1
-
Affiliations:
- Research Institute of Molecular Medicine and Pathobiochemistry, V.F. Voino-Yasenetskii Krasnoyarsk State Medical University
- Issue: Vol 11, No 1 (2017)
- Pages: 34-39
- Section: Original articles
- Submitted: 20.04.2017
- Published: 12.05.2017
- URL: https://annaly-nevrologii.com/journal/pathID/article/view/457
- DOI: https://doi.org/10.18454/ACEN.2017.1.6155
- ID: 457
Cite item
Full Text
Abstract
Introduction. Cerebral endothelial cells express monocarboxylate transporters MCT1 for blood–brain barrier (BBB) transfer of lactate, which are regulated by CD147 activity, as well as lactate receptors GPR81 (HCAR1). Metabolism and intercellular transport of lactate is the crucial mechanism for regulating the function of BBB cells.
Objective. To study the effect of activity of GPR81 receptors in cerebral endothelial cells on expression of MCT1, CD147 and the mitochondrial dynamics, which will make it possible to explain the effect of local production of lactate by perivascular astrocytes on angiogenesis in the cerebral tissue.
Materials and methods. The culture of cerebral endothelial cells isolated from the brain of 15–17-day-old Wistar rat embryos was used in this study. Mitochondrial biogenesis of cerebral endothelial cells was studied using the standard MitoBiogenesis In-Cell ELISA Kit protocol (Abcam). Chemical hypoxia was induced by incubation in the presence of 50 μM iodoacetate for 30 min. 3Cl-5OH-BA (Calbiochem) at concentrations of 5, 50, and 500 μM was used as an agonist of GPR81 lactate receptors during 24 h. The number of cells expressing GPR81, CD147, and MCT1 molecules was evaluated using indirect double-antibody ELISA.
Results. It was found for the first time that prolonged dose-dependent stimulation of GPR81 receptors with 3Cl-5OH-BA intensifies mitochondrial biogenesis (up to 1.5-fold, р<0.05). Meanwhile, a statistically significant (p<0.05) inhibition of expression of monocarboxylate transporters MCT1 (from 81±1.6% to 40.7±4.4%) and the conjugated CD147 protein (from 57.4±3.3% to 48.3±2.9%) in cerebral endothelial cells in the study group compared to the control group.
Conclusions. The findings broaden the range of potential applications of GPR81 agonists for modulating intercellular interactions in a neurovascular unit and controlling the functional activity of cerebral microvessel endothelial cells.
About the authors
E. D. Khilazheva
Research Institute of Molecular Medicine and Pathobiochemistry, V.F. Voino-Yasenetskii Krasnoyarsk State Medical University
Email: allasalmina@mail.ru
Russian Federation, Krasnoyarsk
N. V. Pisareva
Research Institute of Molecular Medicine and Pathobiochemistry, V.F. Voino-Yasenetskii Krasnoyarsk State Medical University
Email: allasalmina@mail.ru
Russian Federation, Krasnoyarsk
A. V. Morgun
Research Institute of Molecular Medicine and Pathobiochemistry, V.F. Voino-Yasenetskii Krasnoyarsk State Medical University
Email: allasalmina@mail.ru
Russian Federation, Krasnoyarsk
E. B. Boitsova
Research Institute of Molecular Medicine and Pathobiochemistry, V.F. Voino-Yasenetskii Krasnoyarsk State Medical University
Email: allasalmina@mail.ru
Russian Federation, Krasnoyarsk
T. E. Taranushenko
Research Institute of Molecular Medicine and Pathobiochemistry, V.F. Voino-Yasenetskii Krasnoyarsk State Medical University
Email: allasalmina@mail.ru
Russian Federation, Krasnoyarsk
O. V. Frolova
Research Institute of Molecular Medicine and Pathobiochemistry, V.F. Voino-Yasenetskii Krasnoyarsk State Medical University
Email: allasalmina@mail.ru
Russian Federation, Krasnoyarsk
Alla B. Salmina
Research Institute of Molecular Medicine and Pathobiochemistry, V.F. Voino-Yasenetskii Krasnoyarsk State Medical University
Author for correspondence.
Email: allasalmina@mail.ru
Russian Federation, Krasnoyarsk
References
- Morgun A.V., Kuvacheva N.V., Khilazheva E.D. et al. [Technology study and modeling of the blood-brain barrier] In: [XXI Century Neurology: diagnostic,treatment and research technologies. Eds. Piradov M.A., Illarioshkin S.N., Tanashyan.M.M.]. Moscow. ATMO, 2015. Vol. 3: P. 134–166. (In Russ.).
- Salmina A.B., Kuvacheva N.V., Morgun A.V. et al. Glycolysis-mediated control of blood-brain barrier development and function. Int. J. Biochem. Cell Biol. 2015; 64: 174–84. doi: 10.1016/j.biocel.2015.04.005. PMID: 25900038.
- De Bock K., Georgiadou M., Carmeliet P. Role of endothelial cell metabolism in vessel sprouting. Cell Metab. 2013; 18: 634–47. DOI: 10.1016/j. cmet.2013.08.001. PMID: 23973331.
- Mugoni V., Postel R., Catanzaro V. et al. Ubiad1 is an antioxidant enzyme that regulates eNOS activity by CoQ10 synthesis. Cell 2013; 152: 504–18. doi: 10.1016/j.cell.2013.01.013. PMID: 23374346.
- Verdegem D., Moens S., Stapor P., Carmeliet P. Endothelial cell metabolism: parallels and divergences with cancer cell metabolism. Cancer Metab. 2014; 2: 19. doi: 10.1186/2049-3002-2-19. PMID: 25250177.
- Figley C.R. Lactate transport and metabolism in the human brain: implications for the astrocyte-neuron lactate shuttle hypothesis. J. Neurosci. 2011; 31: 4768–70. doi: 10.1523/JNEUROSCI.6612-10.2011. PMID: 21451014.
- Pavlides S., Whitaker-Menezes D., Castello-Cros R. et al. The reverse Warburg effect: aerobic glycolysis in cancer associated fibroblasts and the tumor stroma. Cell Cycle 2009; 8: 3984–4001. doi: 10.4161/cc.8.23.10238. PMID: 19923890.
- Jornayvaz F.R., Shulman G.I. Regulation of mitochondrial biogenesis. Essays Biochem. 2010; 47: 69–84. doi: 10.1042/bse0470069. PMID: 20533901.
- Lin X.W., Tang L., Yang J., Xu W.H. HIF-1 regulates insect lifespan extension by inhibiting c-Myc-TFAM signaling and mitochondrial biogenesis. Biochim. Biophys. Acta 2016; 1863: 2594–2603. doi: 10.1016/j.bbamcr.2016.07.007. PMID: 27469241.
- Pérez-Escuredo J., Van Hée V.F., Sboarina M. et al. Monocarboxylate transportersin the brain and in cancer. Biochim. Biophys. Acta 2016; 1863: 2481–97. doi: 10.1016/j.bbamcr.2016.03.013. PMID: 26993058.
- Mosienko V., Teschemacher A.G., Kasparov S. Is L-lactate a novel signaling molecule in the brain? J. Cereb. Blood Flow Metab. 2015; 35: 1069–75. doi: 10.1038/jcbfm.2015.77. PMID: 25920953.
- Bergersen L.H. Lactate transport and signaling in the brain: potential therapeutic targets and roles in body-brain interaction. J. Cereb. Blood Flow Metab. 2015; 35: 176–85. doi: 10.1038/jcbfm.2014.206. PMID: 25425080.
- Khilazheva E.D., Boytsova E.B., Pozhilenkova E.A. et al. [The model of neurovascular unit in vitro consisting of three cells types]. Tsitologiya [Cytology] 2015; 10: 710–713. (In Russ.).
- Halestrap A.P. The monocarboxylate transporter family-Structure and functional characterization. IUBMB Life 2012; 64: 1–9. doi: 10.1002/iub.573. PMID: 22131303.
- Uhernik A.L., Tucker C., Smith J.P. Control of MCT1 function in cerebrovascular endothelial cells by intracellular pH. Brain Res. 2011; 1376: 10–22. doi: 10.1016/j.brainres.2010.12.060. PMID: 21192921.
- Smith J.P., Uhernik A.L., Li L. et al. Regulation of Mct1 by cAMP-dependent internalization in rat brain endothelial cells. Brain Res. 2012; 1480: 1–11. doi: 10.1016/j.brainres.2012.08.026. PMID: 22925948.
- Li S., Nguyen T.T., Bonanno J.A. CD147 required for corneal endothelial lactate transport. Invest. Ophthalmol.Vis. Sci. 2014; 55: 4673–81. DOI: 10.1167/ iovs.14-14386. PMID: 24970254.
- Sameshima T., Nabeshima K., Toole B.P. et al. Correlation of emmprin expression in vascular endothelial cells with blood-brain-barrier function: a study using magnetic resonance imaging enhanced by Gd-DTPA and immunohistochemistry in brain tumors. Virchows Arch. 2003; 442: 577–84. DOI: 10.1007/ s00428-003-0801-7. PMID: 12719975.
- Dang B., Li H., Xu X. et al. Cyclophilin A/Cluster of differentiation 147 interactions participate in early brain injury after subarachnoid hemorrhage in rats. Crit. Care Med. 2015; 43: e369-81. doi: 10.1097/CCM.0000000000001146. PMID: 26132882.
- Schmidt M.M., Dringen R. Differential effects of iodoacetamide and iodoacetate on glycolysis and glutathione metabolism of cultured astrocytes. Front. Neuroenergetics 2009; 1: 1. doi: 10.3389/neuro.14.001.2009. PMID: 19584905.
- LeMaistre J.L., Anderson C.M. Custom astrocyte-mediated vasomotor responses to neuronal energy demand. Genome Biol. 2009; 10: 209. DOI: 10.1186/ gb-2009-10-2-209. PMID: 19232077.
- Roland C.L., Arumugam T., Deng D. et al. Cell surface lactate receptor GPR81 is crucial for cancer cell surviva. Cancer Res. 2014; 74: 5301–10. doi: 10.1158/0008-5472.CAN-14-0319. PMID: 24928781.