Hipertansiyon, oldukca sık rastlanan ve toplum sağlığını onemli derecede tehdit eden bir hastalıktır. Bu konuda fazlaca araştırma yapılmış olmasına rağmen, pek cok etkenin yer aldığı hipertansiyon patogenezi henuz tam olarak anlaşılamamıştır. Gunumuzde, hipertansiyonda klasik semptomatik tedaviler uygulanmaya devam etmektedir. Bu nedenle, hipertansiyon patogenezinin aydınlatılması, secici tedavi stratejilerinin geliştirilmesi acısından oldukca onemlidir. Endoplazmik retikulum (ER), hucresel stresi erken donemde algılayarak yanıt oluşturan bir organeldir. ER, protein sentezi icin kalite kontrol merkezi olarak tanımlanmıştır. Katlanmamış veya yanlış katlanmış proteinler ER'de tutularak degarde edilirken, sadece doğru bir şekilde katlanmış proteinler ER'den cıkmaktadır. ER'nin lumenine katlanmamış ya da yanlış katlanmış proteinlerin birikmesiyle ortaya cıkan durum, endoplazmik retikulum stresi (ERS) olarak adlandırılmaktadır. ER'nin işlev kapasitesini aşan genel protein sentezinin artışı, kalsiyum homeostazı değişimleri, oksidatif stres ve hipoksi gibi bazı patolojiler ERS'ye yol acmaktadır. ERS'nin erken evrelerinde bircok koruyucu ve adaptif yanıt devreye girmektedir. Uzun sureli ERS sonucunda ise hucrede işlev bozuklukları oluşmaktadır. Son zamanlarda, ERS'nin onlenmesi ya da ortadan kaldırılması; hipertansiyon, kalp yetersizliği gibi kardiyovaskuler hastalıkların tedavisinde potansiyel bir hedef olarak one surulmuştur. İlk olarak beyindeki ERS'nin kronik hipertansiyonda anahtar rol oynadığını gosterilmiştir. Daha sonraki yıllarda, hayvanlarda farklı deneysel hipertansiyon modellerinde yapılan calışmalar, ERS'nin hipertansiyon etiyopatogenezindeki rolunu ortaya koymuştur. Bu calışma, kardiyovaskuler sistemde ERS'nin hipertansiyon oluşumu ve gelişimine katkılarını ve ERS'ye yonelik tedavi stratejilerini kapsamaktadır.
Anahtar Kelimeler: Hipertansiyon; endoplazmik retikulum stresi
Hypertension is the most common cardiovascular disease, which is a major threat to public health. Although there has been much research on this subject, the pathogenesis of hypertension, which involves many factors, has not been fully understood. While classic symptomatic treatments continue to be applied, clarification of the pathogenesis of hypertension is important for the development of selective treatment strategies. Endoplasmic reticulum (ER), which responds to cellular stress in an early period, is defined as a quality control center for protein synthesis. Only properly folded proteins are transported from ER while unfolded or misfolded proteins are retained and degraded. Endoplasmic reticulum stress (ERS) is the accumulation of unfolded or misfolded protein in the lumen of the endoplasmic reticulum (ER). It is caused by pathological conditions that overwhelm the functional capacity of the ER, such as an increase in overall protein synthesis, changes in calcium homeostasis, redox imbalance, and hypoxia. Recently, the inhibition or reduction of ERS has been recognized as a potential target for the treatment of cardiovascular diseases, such as hypertension and heart failure. It has been firstly shown that ERS in the brain plays a key role in chronic hypertension. Furthermore, various experimental models have been used to investigate the role of ERS in the pathogenesis of hypertension. This review highlights the role of ERS in the etiopathogenesis of hypertension and the treatment strategies that target ERS.
Keywords: Hypertension; endoplasmic reticulum stress
- Coffman TM. Under pressure: the search for the essential mechanisms of hypertension. Nat Med. 2011;17(11):1402-9. [Crossref] [PubMed]
- Oparil S, Zaman MA, Calhoun DA. Pathogenesis of hypertension. Ann Intern Med. 2003;139(9):761-76. [Crossref] [PubMed]
- Ron D, Walter P. Signal integration in the endoplasmic reticulum unfolded protein response. Nat Rev Mol Cell Biol. 2007;8(7):519-29. [Crossref] [PubMed]
- Zhao L, Ackerman SL. Endoplasmic reticulum stress in health and disease. Curr Opin Cell Biol. 2006;18(4):444-52. [Crossref] [PubMed]
- Sano R, Reed JC. ER stress-induced cell death mechanisms. Biochim Biophys Acta. 2013;1833(12):3460-70. [Crossref] [PubMed] [PMC]
- Han S, Bal NB, Sadi G, Usanmaz SE, Tuglu MM, Uludag MO, et al. Inhibition of endoplasmic reticulum stress protected DOCA-salt hypertension-induced vascular dysfunction. Vascul Pharmacol. 2018;113:38-46. [Crossref] [PubMed]
- Kassan M, Galan M, Partyka M, Saifudeen Z, Henrion D, Trebak M, et al. Endoplasmic reticulum stress is involved in cardiac damage and vascular endothelial dysfunction in hypertensive mice. Arterioscler Throm Vasc Biol. 2012;32(7):1652-61. [Crossref] [PubMed] [PMC]
- Young CN, Cao X, Guruju MR, Pierce JP, Morgan DA, Wang G, et al. ER stress in the brain subfornical organ mediates angiotensin-dependent hypertension. J Clin Invest. 2012;122(11):3960-4. [Crossref] [PubMed] [PMC]
- Schwarz DS, Blower MD. The endoplasmic reticulum: structure, function and response to cellular signaling. Cell Mol Life Sci. 2016;73(1):79-94. [Crossref] [PubMed] [PMC]
- Wang M, Kaufman RJ. Protein misfolding in the endoplasmic reticulum as a conduit to human disease. Nature. 2016;529(7586):326-35. [Crossref] [PubMed]
- Clapham DE. Calcium signaling. Cell. 2007;131(6):1047-58. [Crossref] [PubMed]
- Samtleben S, Jaepel J, Fecher C, Andreska T, Rehberg M, Blum R. Direct imaging of ER calcium with targeted-esterase induced dye loading (TED). J Vis Exp. 2013;(75):e50317. [Crossref] [PubMed] [PMC]
- Berridge MJ, Bootman MD, Roderick HL. Calcium signalling: dynamics, homeostasis and remodelling. Nat Rev Mol Cell Biol. 2003;4(7):517-29. [Crossref] [PubMed]
- Krebs J, Agellon LB, Michalak M. Ca(2+) homeostasis and endoplasmic reticulum (ER) stress: an integrated view of calcium signaling. Biochem Biophys Res Commun. 2015;460(1):114-21. [Crossref] [PubMed]
- Lynch JM, Maillet M, Vanhoutte D, Schloemer A, Sargent MA, Blair NS, et al. A thrombospondin-dependent pathway for a protective ER stress response. Cell. 2012;149(6):1257-68. [Crossref] [PubMed] [PMC]
- Meusser B, Hirsch C, Jarosch E, Sommer T. ERAD: the long road to destruction. Nat Cell Biol. 2005;7(8):766-72. [Crossref] [PubMed]
- Liu MQ, Chen Z, Chen LX. Endoplasmic reticulum stress: a novel mechanism and therapeutic target for cardiovascular diseases. Acta Pharmacol Sin. 2016;37(4):425-43. [Crossref] [PubMed] [PMC]
- Naidoo N. ER and aging-protein folding and the ER stress response. Ageing Res Rev. 2009;8(3):150-9. [Crossref] [PubMed]
- Bravo R, Parra V, Gatica D, Rodriguez AE, Torrealba N, Paredes F, et al. Endoplasmic reticulum and the unfolded protein response: dynamics and metabolic integration. Int Rev Cell Mol Biol. 2013;301:215-90. [Crossref] [PubMed] [PMC]
- Shi YG, Vattem KM, Sood R, An J, Liang J, Stramm L, et al. Identification and characterization of pancreatic eukaryotic initiation factor 2 alpha-subunit kinase, PEK, involved in translational control. Mol Cell Biol. 1998;18(12): 7499-509. [Crossref] [PubMed] [PMC]
- Bertolotti A, Zhang Y, Hendershot LM, Harding HP, Ron D. Dynamic interaction of BiP and ER stress transducers in the unfolded-protein response. Nat Cell Biol. 2000;2(6):326-32. [Crossref] [PubMed]
- Dever TE. Gene-specific regulation by general translation factors. Cell. 2002;108(4):545-56. [Crossref]
- Harding HP, Novoa I, Zhang YH, Zeng H, Wek R, Schapira M, et al. Regulated translation initiation controls stress-induced gene expression in mammalian cells. Mol Cell. 2000;6(5):1099-108. [Crossref]
- Cullinan SB, Zhang D, Hannink M, Arvisais E, Kaufman RJ, Diehl JA. Nrf2 is a direct PERK substrate and effector of PERK-dependent cell survival. Mol Cell Biol. 2003;23(20):7198-209. [Crossref] [PubMed] [PMC]
- Walter P, Ron D. The unfolded protein response: from stress pathway to homeostatic regulation. Science. 2011;334(6059):1081-6. [Crossref] [PubMed]
- Iwawaki T, Hosoda A, Okuda T, Kamigori Y, Nomura-Furuwatari C, Kimata Y, et al. Translational control by the ER transmembrane kinase/ribonuclease IRE1 under ER stress. Nat Cell Biol. 2001;3(2):158-64. [Crossref] [PubMed]
- Tirasophon W, Welihinda AA, Kaufman RJ. A stress response pathway from the endoplasmic reticulum to the nucleus requires a novel bifunctional protein kinase/endoribonuclease (Ire1p) in mammalian cells. Genes Dev. 1998;12(12):1812-24. [Crossref] [PubMed] [PMC]
- Kimata Y, Ishiwata-Kimata Y, Ito T, Hirata A, Suzuki T, Oikawa D, et al. Two regulatory steps of ER-stress sensor Ire1 involving its cluster formation and interaction with unfolded proteins. J Cell Biol. 2007;179(1):75-86. [Crossref] [PubMed] [PMC]
- Hetz C. The unfolded protein response: controlling cell fate decisions under ER stress and beyond. Nat Rev Mol Cell Biol. 2012;13(2):89-102. [Crossref] [PubMed]
- Ron D, Hubbard SR. How IRe1 reacts to ER stress. Cell. 2008;132(1):24-6. [Crossref] [PubMed]
- Puthalakath H, O'Reilly LA, Gunn P, Lee L, Kelly PN, Huntington ND, et al. ER stress triggers apoptosis by activating BH3-only protein Bim. Cell. 2007;129(7):1337-49. [Crossref] [PubMed]
- Yamaguchi H, Wang HG. CHOP is involved in endoplasmic reticulum stress-induced apoptosis by enhancing DR5 expression in human carcinoma cells. J Biol Chem. 2004;279(44): 45495-502. [Crossref] [PubMed]
- Dufey E, Sepulveda D, Rojas-Rivera D, Hetz C. Cellular mechanisms of endoplasmic reticulum stress signaling in health and disease. 1. an overview. Am J Physiol Cell Physiol. 2014;307(7):C582-94. [Crossref] [PubMed]
- Logue SE, Cleary P, Saveljeva S, Samali A. New directions in ER stress-induced cell death. Apoptosis. 2013;18(5):537-46. [Crossref] [PubMed]
- Lenna S, Han R, Trojanowska M. Endoplasmic reticulum stress and endothelial dysfunction. IUBMB Life. 2014;66(8):530-7. [Crossref] [PubMed] [PMC]
- Galan M, Kassan M, Kadowitz PJ, Trebak M, Belmadani S, Matrougui K. Mechanism of endoplasmic reticulum stress-induced vascular endothelial dysfunction. Biochim Biophys Acta. 2014;1843(6):1063-75. [Crossref] [PubMed] [PMC]
- Lau YS, Mustafa MR, Choy KW, Chan SMH, Potocnik S, Herbert TP, et al. 3 ',4 '-dihydroxyflavonol ameliorates endoplasmic reticulum stress-induced apoptosis and endothelial dysfunction in mice. Sci Rep-Uk. 2018;8. [Crossref] [PubMed] [PMC]
- Sarvani C, Sireesh D, Ramkumar KM. Unraveling the role of ER stress inhibitors in the context of metabolic diseases. Pharmacol Res. 2017;119:412-21. [Crossref] [PubMed]
- Chen Y, Liu CP, Xu KF, Mao XD, Lu YB, Fang L, et al. Effect of taurine-conjugated ursodeoxycholic acid on endoplasmic reticulum stress and apoptosis induced by advanced glycation end products in cultured mouse podocytes. Am J Nephrol. 2008;28(6):1014-22. [Crossref] [PubMed]
- Ozcan U, Yilmaz E, Ozcan L, Furuhashi M, Vaillancourt E, Smith RO, et al. Chemical chaperones reduce ER stress and restore glucose homeostasis in a mouse model of type 2 diabetes. Science. 2006;313(5790):1137-40. [Crossref] [PubMed] [PMC]
- Vang S, Longley K, Steer CJ, Low WC. The unexpected uses of Urso- and Tauroursodeoxycholic acid in the treatment of non-liver diseases. Glob Adv Health Med. 2014;3(3):58-69. [Crossref] [PubMed] [PMC]
- Liang B, Wang S, Wang Q, Zhang W, Viollet B, Zhu Y, et al. Aberrant endoplasmic reticulum stress in vascular smooth muscle increases vascular contractility and blood pressure in mice deficient of AMP-activated protein kinase-?2 in vivo. Arterioscler Thromb Vasc Biol. 2013;33(3):595-604. [Crossref] [PubMed] [PMC]
- Spitler KM, Matsumoto T, Webb RC. Suppression of endoplasmic reticulum stress improves endothelium-dependent contractile responses in aorta of the spontaneously hypertensive rat. Am J Physiol Heart Circ Physiol. 2013;305(3):H344-53. [Crossref] [PubMed] [PMC]
- Spitler KM, Webb RC. Endoplasmic reticulum stress contributes to aortic stiffening via proapoptotic and fibrotic signaling mechanisms. Hypertension. 2014;63(3):E40-5. [Crossref] [PubMed] [PMC]
- Takayanagi T, Kawai T, Forrester SJ, Obama T, Tsuji T, Fukuda Y, et al. Role of epidermal growth factor receptor and endoplasmic reticulum stress in vascular remodeling induced by angiotensin II. Hypertension. 2015;65(6): 1349-55. [Crossref] [PubMed] [PMC]
- Choy KW, Mustafa MR, Lau YS, Liu J, Murugan D, Lau CW, et al. Paeonol protects against endoplasmic reticulum stress-induced endothelial dysfunction via AMPK/PPAR delta signaling pathway. Biochem Pharmacol. 2016;116:51-62. [Crossref] [PubMed]
- Carlisle RE, Werner KE, Yum V, Lu C, Tat V, Memon M, et al. Endoplasmic reticulum stress inhibition reduces hypertension through the preservation of resistance blood vessel structure and function. J Hypertens. 2016;34(8): 1556-69. [Crossref] [PubMed]
.: Process List