Reticulon 3 regulates sphingosine-1-phosphate synthesis in endothelial cells to control blood pressure

Abstract

The discovery of the endothelium as a major regulator of vascular tone triggered intense research among basic and clinical investigators to unravel the physiologic and pathophysiologic significance of this phenomenon. Sphingosine-l-phosphate (S1P), derived from the vascular endothelium, is a significant regulator of blood pressure. However, the mechanisms underlying the regulation of S1P biosynthetic pathways in arteries remain to be further clarified. Here, we reported that Reticulon 3 (RTN3) regulated endothelial sphingolipid biosynthesis and blood pressure. We employed public datasets, patients, and mouse models to explore the pathophysiological roles of RTN3 in blood pressure control. The underlying mechanisms were studied in human umbilical vein endothelial cells (HUVECs). We reported that increased RTN3 was found in patients and that RTN3-null mice presented hypotension. In HUVECs, RTN3 can regulate migration and tube formation via the S1P signaling pathway. Mechanistically, RTN3 can interact with CERS2 to promote the selective autophagy of CERS2 and further influence S1P signals to control blood pressure. We also identified an RTN3 variant (c.116C>T, p.T39M) in a family with hypertension. Our data provided the first evidence of the association between RTN3 level changes and blood pressure anomalies and preliminarily elucidated the importance of RTN3 in S1P metabolism and blood pressure regulation.

Keywords

ceramide synthase 2 / ceramides / hypertension / hypotension / reticulon 3 / sphingosine-l-phosphate

References

[1] Cantalupo A, Zhang Y, Kothiya M, et al. Nogo-B regulates endothelial sphingolipid homeostasis to control vascular function and blood pressure. Nat Med. 2015;21(9):1028-1037.

[2] Cartier A, Hla T. Sphingosine 1-phosphate: lipid signaling in pathology and therapy. Science. 2019;366(6463).

[3] Yanagida K, Hla T. Vascular and immunobiology of the circulatory sphingosine 1-phosphate gradient. Annu Rev Physiol. 2017;79:67-91.

[4] Venkataraman K, Lee YM, Michaud J, et al. Vascular endothelium as a contributor of plasma sphingosine 1-phosphate. Circ Res. 2008;102(6):669-676.

[5] Dantas AP, Igarashi J, Michel T. Sphingosine 1-phosphate and control of vascular tone. Am J Physiol Heart Circ Physiol. 2003;284(6):H2045-H2052.

[6] Coussin F, Scott RH, Wise A, Nixon GF. Comparison of sphingosine 1-phosphate-induced intracellular signaling pathways in vascular smooth muscles: differential role in vasoconstriction. Circ Res. 2002;91(2):151-157.

[7] Cantalupo A, Di Lorenzo A. S1P signaling and de novo biosynthesis in blood pressure homeostasis. J Pharmacol Exp Ther. 2016;358(2):359-370.

[8] Pyne S, Adams DR, Pyne NJ. Sphingosine 1-phosphate and sphingosine kinases in health and disease: recent advances. Prog Lipid Res. 2016;62:93-106.

[9] Wegner MS, Schiffmann S, Parnham MJ, Geisslinger G, Grosch S. The enigma of ceramide synthase regulation in mammalian cells. Prog Lipid Res. 2016;63:93-119.

[10] Shi Q, Ge Y, Sharoar MG, et al. Impact of RTN3 deficiency on expression of BACE1 and amyloid deposition. J Neurosci. 2014;34(42):13954-13962.

[11] Zhou J, Shi Q, Ge YY, et al. Reticulons 1 and 3 are essential for axonal growth and synaptic maintenance associated with intellectual development. Hum Mol Genet. 2023;32(16):2587-2599.

[12] Xiang R, Fan LL, Huang H, et al. Increased reticulon 3 (RTN3) leads to obesity and hypertriglyceridemia by interacting with heat shock protein family A (Hsp70) member 5 (HSPA5). Circulation. 2018;138(17):1828-1838.

[13] Grumati P, Morozzi G, Holper S, et al. Full length RTN3 regulates turnover of tubular endoplasmic reticulum via selective autophagy. eLife. 2017;6.

[14] Caldieri G, Barbieri E, Nappo G, et al. Reticulon 3-dependent ER-PM contact sites control EGFR nonclathrin endocytosis. Science. 2017;356(6338):617-624.

[15] Fan LL, Du R, Liu JS, et al. Loss of RTN3 phenocopies chronic kidney disease and results in activation of the IGF2-JAK2 pathway in proximal tubular epithelial cells. Exp Mol Med. 2022;54(5):653-661.

[16] Song S, Shi Y, Wu W, et al. Reticulon 3-mediated Chk2/p53 activation suppresses hepatocellular carcinogenesis and is blocked by hepatitis B virus. Gut. 2021;70(11):2159-2171.

[17] Wang Q, Song X, Du S, et al. Multiple trajectories of body mass index and waist circumference and their associations with hypertension and blood pressure in Chinese adults from 1991 to 2018: a prospective study. Nutrients. 2023;15(3).

[18] TCS Keller, t, Lechauve C, Keller AS, et al. The role of globins in cardiovascular physiology. Physiol Rev. 2022;102(2):859-892.

[19] Zhu G, Chen H, Zhang W. Phenotype switch of vascular smooth muscle cells after siRNA silencing of filamin. Cell Biochem Biophys. 2011;61(1):47-52.

[20] Kotini MP, van der Stoel MM, Yin J, et al. Vinculin controls endothelial cell junction dynamics during vascular lumen formation. Cell Rep. 2022;39(2):110658.

[21] Feng HZ, Wang H, Takahashi K, Jin JP. Double deletion of calponin 1 and calponin 2 in mice decreases systemic blood pressure with blunted length-tension response of aortic smooth muscle. J Mol Cell Cardiol. 2019;129:49-57.

[22] Tawa H, Rikitake Y, Takahashi M, et al. Role of afadin in vascular endothelial growth factor- and sphingosine 1-phosphate-induced angiogenesis. Circ Res. 2010;106(11):1731-1742.

[23] French KJ, Zhuang Y, Maines LW, et al. Pharmacology and antitumor activity of ABC294640, a selective inhibitor of sphingosine kinase-2. J Pharmacol Exp Ther. 2010;333(1):129-139.

[24] Meissner A, Miro F, Jimenez-Altayo F, Jurado A, Vila E, Planas AM. Sphingosine-1-phosphate signalling-a key player in the pathogenesis of angiotensin II-induced hypertension. Cardiovasc Res. 2017;113(2):123-133.

[25] Grumati P, Dikic I, Stolz A. ER-phagy at a glance. J Cell Sci. 2018;131(17).

[26] Benjamin EJ, Virani SS, Callaway CW, et al. Heart disease and stroke statistics-2018 update: a report from the American Heart Association. Circulation. 2018;137(12):e67-e492.

[27] Gerdts E, Sudano I, Brouwers S, et al. Sex differences in arterial hypertension. Eur Heart J. 2022;43(46):4777-4788.

[28] Theilmeier G, Schmidt C, Herrmann J, et al. High-density lipoproteins and their constituent, sphingosine-1-phosphate, directly protect the heart against ischemia/reperfusion injury in vivo via the S1P3 lysophospholipid receptor. Circulation. 2006;114(13):1403-1409.

[29] Rosen H, Goetzl EJ. Sphingosine 1-phosphate and its receptors: an autocrine and paracrine network. Nat Rev Immunol. 2005;5(7):560-570.

[30] Chen W, Wu C, Chen Y, et al. Downregulation of ceramide synthase 1 promotes oral cancer through endoplasmic reticulum stress. Int J Oral Sci. 2021;13(1):10.

[31] Yamaji T, Horie A, Tachida Y, et al. Role of intracellular lipid logistics in the preferential usage of very long chain-ceramides in glucosylceramide. Int J Mol Sci. 2016;17(10).

[32] Lee SY, Hong IK, Kim BR, et al. Activation of sphingosine kinase 2 by endoplasmic reticulum stress ameliorates hepatic steatosis and insulin resistance in mice. Hepatology. 2015;62(1):135-146.

[33] Ishimaru K, Yoshioka K, Kano K, et al. Sphingosine kinase-2 prevents macrophage cholesterol accumulation and atherosclerosis by stimulating autophagic lipid degradation. Sci Rep. 2019;9(1):18329.

[34] Czopek A, Moorhouse R, Gallacher PJ, et al. Endothelin blockade prevents the long-term cardiovascular and renal sequelae of acute kidney injury in mice. Sci Transl Med. 2022;14(675):eabf5074.

[35] Zou Y, He W, Wang K, et al. Identification of rare RTN3 variants in Alzheimer's disease in Han Chinese. Hum Genet. 2018;137(2):141-150.

[36] Martinez-Ramirez M, Madero M, Vargas-Alarcon G, et al. HDL-sphingomyelin reduction after weight loss by an energy-restricted diet is associated with the improvement of lipid profile, blood pressure, and decrease of insulin resistance in overweight/obese patients. Clin Chim Acta. 2016;454:77-81.

[37] Cantalupo A, Sasset L, Gargiulo A, et al. Endothelial sphingolipid de novo synthesis controls blood pressure by regulating signal transduction and NO via ceramide. Hypertension. 2020;75(5):1279-1288.

[38] Zhang N, Zhang Y, Miao W, et al. An unexpected role for BAG3 in regulating PARP1 ubiquitination in oxidative stress-related endothelial damage. Redox Biol. 2022;50:102238.

[39] Jin JY, Wu PF, Luo FM, et al. GLIS family zinc finger 1 was first linked with preaxial polydactyly i in humans by stepwise genetic analysis. Front Cell Dev Biol. 2021;9:781388.

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