Diyabetik Kardiyomiyopati ve Prolil Hidroksilazlar

Year 2017, Volume: 70 Issue: 1, 29 - 36, 21.04.2017

Fırat Akat

https://doi.org/10.1501/Tipfak_0000000961

Abstract

Diyabetik kardiyomiyopati (DKMP), diyabet hastalarında koroner arter hastalığı ve hipertansiyondan bağımsız olarak gelișen ventriküler disfonksiyon olarak ifade edilmektedir. Kalp dokusunda görülen, intersitisyal fibrozis, miyosit hipertrofisi ve artmıș kontraktil protein glikozilasyonu DKMP’de görülen kardiyak patolojilere örnek teșkil eder. Sistolik disfonksiyon DKMP’de genellikle geç ve belirgin diyastolik disfonksiyonu olan hastalarda görülen bir bulgudur.

DKMP’nin birçok bașlıktan olușan oldukça karmașık bir patofizyolojisi vardır. Bu derlemede prolil hidroksilazların da içerisinde bulunduğu HIF-VEGF-anjiyogenez aksındaki bozulmalar üzerinde yoğunlașılmıștır. Diyabette hipoksiye verilen HIF yanıtının bozulduğu ve bu değișimin DKMP’nin patogenezinde önemli bir yer tuttuğu bilinmektedir.

Prolil hidroksilazlar (PHD’ler), moleküler oksijeni kofaktör olarak kullanan, oksijen varlığında HIF-α (hipoksi ile indüklenen faktör-α) altbirimini degrade eden enzim yapılı moleküllerdir. Hücresel oksijen homeostazında ve hipoksiye verilen HIF cevabında önemli bir yere sahiptirler. Hipoksik koșullarda PHD enzimi inaktif hale gelir ve degradasyondan kurtulan HIF-1α, β alt birimi ile birleșerek HIF-1 molekülünü olușturur. Bu olaya “HIF stabilizasyonu” adı verilir. Stabilize olan HIF-1 molekülü hücredeki birçok proteinin transkripsiyonunu modifiye eder. HIF’in alt hedeflerinin aktivasyonu hücrenin enerji ve oksijen tüketimini azaltır ve hücreye oksijen arzını arttırır, böylece hipoksik sürecin en az hasarla atlatılması sağlanır.

HIF aktivasyonu sonucu açığa çıkan genomik profilin DKMP’de koruyucu etkileri olduğu bilinmektedir. HIF sistemini aktive etmek için HIF overekspresyonu yapılan genetik modeller, hipoksi uygulaması, PHD inhibitörleri ve PHD geninin susturulması gibi yöntemler kullanılmaktadır.

Literatürde diyabetin PHDlere olan etkisi ile ilgili az sayıda çalıșma bulunmaktadır. Diyabette PHD merkezli araștırmaların artması diyabette önleyici ve tedavi edici stratejilerin geliștirilmesi açısından önemli bilgiler üretilmesine açık bir alandır. 

Keywords

Diyabetik Kardiyomiyopati, Prolil hidroksilazlar, Hipoksi

References

• 1. Melmed S, Polonsky KS, Larsen PR, et al. William's Textbook of Endocrinology, 13th edition., Phidelphia: Elsevier/Saunders. 2016; 1371–1435.
• 2. Lambert P, Bingley PJ. What is Type 1 Diabetes? Medicine 2002; 30: 1–5.
• 3. IDF (International Diabetes Federation). International Diabetes Atlas 2015; ISBN: 978-2-930229-81-2.
• 4. Murarka S, Mohaved MR. Diabetic Cardiomyopathy. Journal of Cardiac Failure 2010: 16(12): 971-979.
• 5. Rubler S, Dlugash J, Yuceoglu YZ, et al. New type of cardiomyopathy associated with diabetic glomerulosclerosis. Am J Cardiol 1972; 30(6): 595-602.
• 6. Devereux RB, Roman MJ, Paranicas M, et al. Impact of diabetes on cardiac structure and function: the Strong Heart Study. Circulation 2000; 101: 2271-2276.
• 7. Kannel WB, Hjortland M, Castelli WP. Role of diabetes in congestive heart failure: the Framingham study. Am J Cardiol 1974; 34: 29-34.
• 8. Das AK, Das JP, Chandrasekar S. Specific heart muscle disease in diabetes mellitus functional structural correlation. Int J Cardiol 1987; 17: 299-302.
• 9. Nunoda S, Genda A, Sugihara N, et al. Quantitative approach to the histopathology of the biopsied right venticlular myocardium in patients with diabetes mellitus. Heart Vessels 1985; 1: 43-47.
• 10. Syrovy I, Hodny Z. Nonenzymatic glycosylation of myosin: effects of diabetes and ageing. Gen Physiol Biophys 1992; 11: 301-307.
• 11. Hayat SA, Patel B, Khattar RS, et al. Diabetic cardiomyopathy: mechanisms diagnosis and treatment. Clinical Science 2004; 107: 539-557.
• 12. Regan TJ, Lyons MM, Ahmed SS, et al. Evidence for cardiomyopathy in familial diabetes mellitus. J Clin Invest 1977; 60: 884-899.
• 13. Mildenberger RR Bar-Shlomo B, Druck MN, et al. Clinically unrecognized dysfunction in young diabetic patients. J Am Coll Cardiol 1984; 4: 234-238.
• 14. Yılmaz S, Canpolat U, Aydoğdu S, et al. Diabetic Cardiomyopathy; Summary of 41 Years. Korean Circ J 2015; 45(4):266-272.
• 15. Trachanas K, Sideris S, Aggeli C, et al. Diabetic Cardiomyopathy: From Pathophysiology to Treatment. Hellenic J Cardiol 2014; 55: 411-421.
• 16. Huynh K, Bernardo BC, McMullen JR, et al. Diabetic cardiomyopathy: Mechanisms and new treatment strategies targeting antioxidant signaling pathways. Pharmacology & Therapeutics 2014; 142: 375–415.
• 17. Joffe II, Travers KE, Perreault-Micale CL, et al. Abnormal cardiac function in the streptozotocin-induced, non–insulin-dependent diabetic rat. J Am Coll Cardio 1999; 34: 2111-2119.
• 18. Kanagy NL. Vascular effects of intermittent hypoxia. ILAR J 2009; 50(3): 282-288.
• 19. Hoit BD, Castro C, Bultron G, et al. Noninvasive evaluation of cardiac dysfunction by echocardiography in streptozotocin-induced diabetic rats. J Card Fail 1999; 5: 324-333.
• 20. Lahaye SLD, Delamarche AG, Malardé L, et al. Intense exercise training induces adaptation in expression and responsiveness of cardiac β-adrenoceptors in diabetic rats. Cardiovascular Diabetology 2010; 9: 72-81.
• 21. Yu J, Fei J, Azad J, et al. Myocardial Protection by Salvia miltiorrhiza Injection in Streptozotocin induced Diabetic Rats through Attenuation of Expression of Thrombospondin-1 and Transforming Growth Factor-β1. The Journal Of International Medical Research 2012; 40: 10161024.
• 22. Cao J, Vecoli C, Neglia D, et al. CobaltProtoporphyrin Improves Heart Function by Blunting Oxidative Stress and Restoring NO Synthase Equilibrium in an Animal Model of Experimental Diabetes. Front Physiol 2012; 3: 1-9.
• 23. Bento CF, Pereira P. Regulation of hypoxia-inducible factor 1 and the loss of the cellular response to hypoxia in diabetes. Diabetologia 2011; 54: 1946–1956.
• 24. Catrina SB. Impaired hypoxia-inducible factor (HIF) regulation by hyperglycemia. J Mol Med 2014; 92: 1025–1034.
• 25. Xiao H, Gu Z, Wang G, et al. The Possible Mechanisms Underlying the Impairment of HIF-1α Pathway Signaling in Hyperglycemia and the Beneficial Effects of Certain Therapies. Int J Med Sci 2013; 10: 14121421.
• 26. Ceradini DJ, Yao D, Grogan RH et al. Decreasing intracellular superoxide corrects defective ischemia-induced new vessel formation in diabetic mice. J Biol Chem 2008; 283:10930–10938.
• 27. Thangarajah H, Yao D, Chang EI et al. The molecular basis for impaired hypoxiainduced VEGF expression in diabetic tissues. Proc Natl Acad Sci USA 2009; 106:13505–13510.
• 28. Bento CF, Fernandes R, Ramalho J et al. The chaperonedependent ubiquitin ligase CHIP targets HIF-1α for degradation in the presence of methylglyoxal. PLoS ONE 2010; 5:e15062
• 29. Kozhukhar AV, Yasinska IM, Sumbayev VV. Nitric oxide inhibits HIF-1 alpha protein accumulation under hypoxic conditions: implication of 2-oxoglutarate and iron. Biochimie 2006; 88: 411–418.
• 30. Botusan IR, Sunkari VG, Savu O, et al. Stabilization of HIF-1α is critical to improve wound healing in diabetic mice. Proc Natl Acad Sci U S A. 2008; 105:1942619431.
• 31. Semenza GL, Wang GL. A nuclear factor induced by hypoxia via de novo protein synthesis binds to the human erythropoietin gene enhancer at a site required for transcriptional activation. Mol Cell Biol 1992; 12: 5447–5454.
• 32. Semenza GL, Wang GL. Characterization of hypoxia-inducible factor 1 and regulation of DNA binding activity by hypoxia. J Biol Chem 1993; 268(29): 21513-8.
• 33. Jiang Bh, Semenza Gl, Bauer C, et al. Hypoxia-inducible factor 1 levels vary exponentially over a physiologically relevant range of O2 tension. Am J Physiol 1996; 271: 1172–1180.
• 34. Ivan M, Kondo K, Yang H, et al. HIF alpha targeted for VHL-mediated destruction by proline hydroxylation: implications for O2 sensing. Science 2001; 292: 464– 468.
• 35. Jaakkola P, Mole DR, Tian YM, et al. Targeting of HIF-alpha to the von HippelLindau ubiquitylation complex by O2-regulated prolyl hydroxylation. Science 2001; 292: 468–472.
• 36. Salceda S, Caro J. Hypoxia-inducible factor 1alpha (HIF-1 alpha) protein is rapidly degraded by the ubiquitin-proteasome system under normoxic conditions. Its stabilization by hypoxia depends on redox induced changes. J Biol Chem 1997; 272: 22642–22647.
• 37. Jeong JW, Bae MK, Ahn MY, et al. Regulation and destabilization of HIF-1 alpha by ARD1-mediated acetylation. Cell 2002; 111: 709–720.
• 38. Tanimoto K, Makino Y, Pereira T, et al. Mechanism of regulation of the hypoxiainducible factor-1 alpha by the von Hippel-Lindau tumor suppressor protein. EMBO J 2000; 19: 4298–4309.
• 39. Cockman ME, Masson N, Mole DR, et al. Hypoxia inducible factor-alpha binding and ubiquitylation by the von Hippel-Lindau tumor suppressor protein. J Biol Chem 2000; 275: 25733–25741.
• 40. Rabinowitz MH. Inhibition of HypoxiaInducible Factor Prolyl Hydroxylase Domain Oxygen Sensors: Tricking the Body into Mounting Orchestrated Survival and Repair Responses. J Med Chem 2013; 56: 9369−9402.
• 41. Semenza GL, Agani F, Booth G, et al. Structural and functional analysis of hypoxia-inducible factor 1. Kidney Int 1997; 51: 553–555.
• 42. Berra E,Ginouvés A, Pouysségur J. The hypoxia-inducible-factor hydroxylases bring fresh air into hypoxia signalling. EMBO Reports 2006; 7(1): 41-45.
• 43. Epstein AC, Gleadle JM, McNeill LA, et al. C. Elegans EGL-9 and mammalian homologs define a family of dioxygenases that regulate HIF by prolyl hydroxylation. Cell 2001;107: 43–54.
• 44. Oehme F, Ellinghaus P, Kolkhof P, et al. Overexpression of PH-4, a novel putative proline 4-hydroxylase, modulates activity of hypoxia inducible transcription factors. Biochem Biophys Res Commun 2002; 296: 343–349.
• 45. Willam C, Maxwell PH, Nichols L, et al. HIF prolyl hydroxylases in the rat; organ distribution and changes in expression following hypoxia and coronary artery ligation. J Mol Cell Cardiol 2006; 41: 68–77.
• 46. Berra E, Benizri E, Ginouvès A, et al. HIF prolyl-hydroxylase 2 is the key oxygen sensor setting low steady-state levels of HIF1α in normoxia. EMBO J 2003; 22: 4082– 4090.
• 47. Berra E, Roux D, Richard DE, et al. Hypoxia-inducible factor-1α (HIF-1α) escapes O2-driven proteasomal degradation irrespective of its subcellular localization: nucleus or ctyoplasm. EMBO Reports 2001; 2(7): 615-620.
• 48. Katschinski DM. In vivo functions of the prolyl-4-hydroxylase domain oxygen sensors: direct route to the treatment of anaemia and the protection of ischaemic tissues. Acta Physiol 2009; 195: 407–414.
• 49. Tian YM, Mole DR, Ratcliffe PJ, et al. Characterization of different isoforms of the HIF prolyl hydroxylase PHD1 generated by alternative initiation. Biochem J 2006; 397: 179–186.
• 50. Zhang Q, Gu J, Li L, et al. Control of cyclin D1 and breast tumorigenesis by the EglN2 prolyl hydroxylase. Cancer Cell 2009; 16: 413–424.
• 51. Metzen E, Stiehl DP, Doege K, et al. Regulation of the prolyl hydroxylase domain protein 2 (phd2/egln-1) gene: identification of a functional hypoxia-responsive element. Biochem J 2005; 387: 711–717.
• 52. Stiehl DP, Wirthner R, Köditz J, et al. Increased prolyl 4-hydroxylase domain proteins compensate for decreased oxygen levels. Evidence for an autoregulatory oxygen-sensing system. J Biol Chem 2006; 281: 23482–23491.
• 53. Appelhoff RJ, Tian YM, Raval RR, et al. Differential function of the prolyl hydroxylases PHD1, PHD2, and PHD3 in the regulation of hypoxia-inducible factor. J Biol Chem 2004; 279: 38458–38465.
• 54. Cervera AM, Apostolova N, Luna-Crespo F, et al. An alternatively spliced transcript of the PHD3 gene retains prolyl hydroxylase activity. Cancer Lett 2006; 233: 131– 138.
• 55. Place TL, Domann FE. Prolyl-hydroxylase 3: Evolving roles for an ancient signaling protein. Hypoxia 2013; 2013: 13–17.
• 56. Luo W, Lin B, Wang Y, et al. PHD3-mediated prolyl hydroxylation of nonmuscle actin impairs polymerization and cell motility. Mol. Biol. Cell 2014; 25: 2788–2796.
• 57. Luo W, Hu H, Chang R, et al. Pyruvate kinase M2 is a PHD3-stimulated coactivator for hypoxia-inducible factor 1. Cell 2011; 145: 732–744.
• 58. Garvalov BK, Foss F, Henze AT, et al. PHD3 regulates EGFR internalization and signalling in tumours. Nat Commun 2014; 5: 5577.
• 59. Huang J, Zhao Q, Mooney SM, et al. Sequence determinants in hypoxia-inducible factor-1α for hydroxylation by the prolyl hydroxylases PHD1, PHD2, and PHD3. J Biol Chem 2002; 277: 39792–39800.
• 60. Tuckerman JR, Zhao Y, Hewitson KS, et al. Determination and comparison of specific activity of the HIF-prolyl hydroxylases. FEBS Lett 2004; 576(1-2): 145-150.
• 61. Chan DA, Sutphin PD, Yen SE et al. Coordinate regulation of the oxygen-dependent degradation domains of hypoxia-inducible factor 1a. Mol Cell Biol 2005; 25: 6415–6426.
• 62. Tekin D, Dursun AD, Xi L. Hypoxia inducible factor 1 (HIF-1) and cardioprotection. 2010; Acta Pharmacologica Sinica 31: 1085–1094.
• 63. Cai Z, Manalo DJ, Wei G, et al. Hearts from rodents exposed to intermittent hypoxia or erythropoietin are protected against ischemia–reperfusion injury. Circulation 2003; 108: 79–85.
• 64. Cai Z, Zhong H, Bosch-Marce M et al. Complete loss of ischaemic preconditioning-induced cardioprotection in mice with partial deficiency of HIF-1 alpha. Cardiovasc Res 2008; 77(3): 463–470.
• 65. Kido M, Du L, Sullivan CC, et al. Hypoxia-Inducible Factor 1-Alpha Reduces Infarction and Attenuates Progression of Cardiac Dysfunction After Myocardial Infarction in the Mouse. JACC 2005; 46(11): 2116–2124.
• 66. Date T, Mochizuki S, Belanger AJ, et al. Expression of constitutively stable hybrid hypoxia-inducible factor-1alpha protects cultured rat cardiomyocytes against simulated ischemia-reperfusion injury. Am J Physiol Cell Physiol 2005; 288: 314–20.
• 67. Shizukuda Y, Mallet Rt, Lee SC, et al. Hypoxic preconditioning of ischaemic canine myocardium. Cardiovasc Res 1992; 26(5): 534–542.
• 68. Verges S, Chacaroun S, Ribout-Godin D, et al. Hypoxic conditioning as a new therapeutic modality. Front Pediatr 2015; 3(58): 1-14.
• 69. Faramoushi M, Sasan RA, Sarraf VS, et al. Cardiac fibrosis and down regulation of GLUT4 in experimental diabetic cardiomyopathy are ameliorated by chronic exposures to intermittent altitude. J Cardiovasc Thorac Res 2016; 8(1): 26-33.
• 70. Akat F. Deneysel Tip I Diyabette Aralıklı Hipoksinin Sol Ventrikül Fonksiyonları Üzerine Etkisinin İncelenmesi. Danışman: Prof.Dr. Hakan FIÇICILAR. 2016; 10132926 nolu Fizyoloji Doktora Tezi.
• 71. Xi L, Taher M, Yin C, et al. Cobalt chloride induces delayed cardiac preconditioning in mice through selective activation of HIF-1alpha and AP-1 and iNOS signaling. Am J Physiol Heart Circ Physiol 2004; 287: 2369–2375.
• 72. Ockaili R, Natarajan R, Salloum F, et al. HIF-1 activation attenuates postischemic myocardial injury: role for heme oxygenase-1 in modulating microvascular chemokine generation. Am J Physiol Heart Circ Physiol 2005; 289: 542–548.
• 73. Bao W, Qin P, Needle S, et al. Chronic inhibition of hypoxia-inducible factor (hif) prolyl 4-hydroxylase improves ventricular performance, remodeling and vascularity following myocardial infarction in the rat. J Cardiovasc Pharmacol 2010; 56(2): 147155.
• 74. Tan T, Luciano JA, Scholz PM, et al. Hypoxia inducible factor-1 improves the actions of positive inotropic agents in stunned cardiac myocytes. Clin Exp Pharmacol Physiol 2009; 36: 904–11.
• 75. Natarajan R, Salloum FN, Fisher BJ, et al. Hypoxia inducible factor-1 activation by prolyl 4-hydroxylase-2 gene silencing attenuates myocardial ischemia reperfusion injury. Circ Res 2006; 98: 133–40.
• 76. Thirunavukkarasu M, Selvaraju V, Dunna NR, et al. Simvastatin treatment inhibits hypoxia inducible factor 1-alpha-(HIF1alpha)-prolyl-4- hydroxylase 3 (PHD-3) and increases angiogenesis after myocardial infarction in streptozotocin-induced diabetic rat. International Journal of Cardiology 2013; 168: 2474–2480.
• 77. Xia Y, Gong L, Liu H, et al. Inhibition of prolyl hydroxylase 3 ameliorates cardiac dysfunction in diabetic cardiomyopathy. Molecular and Cellular Endocrinology 2015; 403: 21–29