Hyperhomocysteinemia Transcriptionally Regulates Expression of a Set of Ion Channels in Brain and Heart Tissues in Mice
Öz
The alterations of ion channel gene expressions in brain and heart tissues in HHcy have not been previously reported. We investigated the mRNA expression levels in brain and heart tissues of the HHcy mice compared to the control mice to characterize distinct expression of 36 ion channels. C57BL/6 J. mice were divided into two groups of 15 animals each: (1) control group and (2) HHcy group. The HHcy was induced by methionine administiration. The mRNA levels of ion channels were analyzed using qRT-PCR. TUNEL staining and MDA assay were used for verification of the negative side effects of HHcy in heart and brain tissues. RT-PCR revealed the upregulation of Hcn4, Trpc3, Trpm2 and the downregulation of Abbc8, Cacna1b, Cacna1c, Cacna1e, Cacna1h, Hcn1, Kcnc3, Kcnh7, Kcnj8, Trpc4, Trpc5, Trpc6, Trpm3, Trpm4, Trpv4, Trpv6 in brain tissues of the HHcy group compared to the control. The upregulation of ion channel expressions in heart tissues were not detected, but we found only the downregulation of Accn1, Accn2, Accn3, Hcn1, Kcnc4 and Trpv6 ion channels. Apoptozis and MDA level were significantly increased in brain and heart tissues of the HHcy group compared to the control. Brain tissues compared to heart tissues exhibit a very considerable and diverse ion channel gene expression pattern in mice with HHcy than control. Clarifying the roles of ion channels in HHcy could shed light on the development of novel therapeutic strategies and ultimately improve HHcy side effects.
Anahtar Kelimeler
Acid-Sensing Ion Channels Transient Receptor Potential Channels Hyperhomocysteinemia Calcium Channels Potassium Channels
Destekleyen Kurum
Firat University Scientific Research Unit (FUBAP)
Proje Numarası
TF.11.67
Teşekkür
We thank to the Firat University Scientific Research Unit (FUBAP) for funding this Project (Project Grant No: TF.11.67)
Kaynakça
- 1. Pan JA, Fan Y, Gandhirajan RK, et al. Hyperactivation of the mammalian degenerin MDEG promotes caspase-8 activation and apoptosis. J Biol Chem. 2013;288(1):2952-63.
- 2. Boldyrev A, Bryushkova E, Mashkina A, et al. Why is homocysteine toxic for the nervous and immune systems? Curr Aging Sci. 2013;6(1):29-36.
- 3. Catterall WA, Dib-Hajj S, Meisler MH, et al. Inherited neuronal ion channelopathies: new windows on complex neurological diseases. J Neurosci. 2008;12(28):11768-77.
- 4. McClenaghan C, Hanson A, Sala-Rabanal, et al. Cantu syndrome associated SUR2 (ABCC9) mutations in distinct structural domains result inKATP channel gain-of-function by differential mechanisms. J Biol Chem. 2018;6:2041-52.
- 5. Ertel EA, Campbell KP, Harpold MM, et al. Nomenclature of voltage-gated calcium channels. Neuron. 2000;25:533-5.
- 6. Wahl-Schott C and Biel M. HCN channels: structure, cellular regulation and physiological function. Cell Mol Life Sci. 2009;66:470-94.
- 7. Jenkinson DH. Potassium channels - multiplicity and challenges. Br J Pharmacol. 2006;147:63-7.
- 8. Morelli MB, Amantini C, Liberati S, et al. TRP channels: new potential therapeutic approaches in CNS neuropathies. CNS Neurol Disord Drug Targets. 2013;12(1):274-93.
- 9. Song YS, Rosenfeld ME. Methionine-induced hyperhomocysteinemia promotes superoxide anion generation and NFkappaB activation in peritoneal macrophages of C57BL/6 mice. J Med Food. 2004;7(2):229-34.
- 10. Liu D, Scholze A, Zhu Z, et al. Increased transient receptor potential channel TRPC3 expression in spontaneously hypertensive rats. Am J Hypertens. 2005;18:1503-7.
- 11. Yagi K. Lipid peroxides and related radicals in clinical medicineIn: Free radicals in diagnostic medicine. Armstrong D, ed New York, Plenum Pres. 1994;1-15.
- 12. Lipton SA, Kim WK, Choi YB, et al. Neurotoxicity associated with dual actions of homocysteine at the N-methyl-D-aspartate receptor. Proc Natl Acad Sci USA. 1997;27: 5923-8.
- 13. Kruman II, Culmsee C, Chan SL, et al. Homocysteine elicits a DNA damage response in neurons that promotes apoptosis and hypersensitivity to excitotoxicity. J Neurosci. 2000;15: 6920-6.
- 14. Miller BA. The role of TRP channels in oxidative stress-induced cell death. J Membr Biol. 2006;209:31-41.
- 15. Simon F, Leiva-Salcedo E, Armisén R, et al. Hydrogen peroxide removes TRPM4 current desensitization conferring increased vulnerability to necrotic cell death. J Biol Chem. 2010;285(26):37150-8.
- 16. Weekman EM, Woolums AE, Sudduth TL, et al. Hyperhomocysteinemia-induced gene expression changes in the cell types of the brain. ASN Neuro. 2017;9(6):1759091417742296.
- 17. Patterson S, Scullion SM, McCluskey JT, et al. Prolonged exposure to homocysteine results in diminished but reversible pancreatic beta-cell responsiveness to insulinotropic agents. Diabetes Metab Res Rev. 2007;4:324-34.
- 18. Scherer EB, Schmitz F, Vuaden FC, et al. Mild hyperhomocysteinemia alters extracellular adenine metabolism in rat brain. Neuroscience. 2012;223:28-34.
- 19. Ashcroft SJ, Ashcroft FM. Properties and functions of ATP-sensitive K-channels. Cell Signal. 1990;2:197–214.
- 20. Phelan KD, Shwe UT, Abramowitz J, et al. Canonical transient receptor channel 5 (TRPC5) and TRPC1/4 contribute to seizure and excitotoxicity by distinct cellular mechanisms. Mol Pharmacol. 2013;83:429-38.
- 21. Distrutti E and Mencarelli A. The methionine connection: homocysteine and hydroge sulfide exert opposite effects on hepatic microcirculation in rats. Hepatology. 2008;2:659-67.
- 22. Budni J, Freitas AE, Binfaré RW, et al. Role of potassium channels in the antidepressant-like effect of folic acid in the forced swimming test in mice. Pharmacol Biochem Behav. 2012;1:148-54.
- 23. Biel M, Wahl-Schott C, Michalakis S, et al. Hyperpolarization-activated cation channels: from genes to function. Physiol Rev. 2009;89:847–85.
- 24. Sohn JW. Ion channels in the central regulation of energy and glucose homeostasis. Front Neurosci. 2013;23:85.
- 25. Selvaraj S, Sun Y, Singh BB. TRPC channels and their implication in neurological diseases. CNS Neurol Disord Drug Targets. 2010;9:94-104.
- 26. Li H, Huang J, Du W, et al. TRPC6 inhibited NMDA receptor activities and protected neurons from ischemic excitotoxicity. J Neurochem. 2010;123:1010-8.
- 27. Roedding AS, Tong SY, Au-Yeung W, et al. Chronic oxidative stress modulates TRPC3 and TRPM2 channel expression and function in rat primary cortical neurons: relevance to the pathophysiology of bipolar disorder. Brain Res. 2013;23:16-27.
- 28. Lee CR, Machold RP, Witkovsky P, et al. TRPM2 channels are required for NMDA-induced burst firing and contribute to H(2)O(2)-dependent modulation in substantia nigra pars reticulata GABAergic neurons. J Neurosci. 2013;16:1157-68.
- 29. Gerzanich V, Woo SK, Vennekens R, et al. De novo expression of Trpm4 initiates secondary hemorrhage in spinal cord injury. Nat Med. 2009;2:185-91.
- 30. Baron A, Diochot S, Salinas M, et al. Venom toxins in the exploration of molecular, physiological and pathophysiological functions of acid-sensing ion channels Toxicon. 2013;1:187-204.
- 31. Gibbons DD, Kutschke WJ, Weiss RM, et al. Heart failure induces changes in acid-sensing ion channels in sensory neurons innervating skeletal muscle. J Physiol. 2015;20:4575-87.
- 32. Moshal KS, Metreveli N, Frank I, et al. Mitochondrial MMP activation, dysfunction and arrhythmogenesis in hyperhomocysteinemia. Curr Vasc Pharmacol. 2008;6:84-92.
- 33. Cheng CF, Chen IL, Cheng MH, et al. Acid-sensing ion channel 3, but not capsaicin receptor TRPV1, plays a protective role in isoproterenol-induced myocardial ischemia in mice. Circ J. 2011;75:174-8.
- 34. Richter TA, Dvoryanchikov GA, Roper SD, et al. Acid-sensing ion channel-2 is not necessary for sour taste in mice. J Neurosci. 2004;21:4088-91.
- 35. Le Bouter S, Demolombe S, Chambellan A, et al. Microarray analysis reveals complex remodeling of cardiac ion channel expression with altered thyroid status: relation to cellular and integrated electrophysiology. Circ Res. 2003;2:234-42.
- 36. Fenske S, Krause SC, Hassan SI, et al. Sick sinus syndrome in HCN1-deficient mice. Circulation. 2013;24:2585-94.
- 37. Grant AO. Cardiac Ion Channels. Circ Arrhythmia Electrophysiol. 2009;2:185-194.
Hiperhomosisteinemi, Farelerde Beyin ve Kalp Dokularında Bir İyon Kanalları Kümesinin Ekspresyonunu Transkripsiyonel Olarak Düzenler
Öz
Hiperhomosisteinemide (HHcy) beyin ve kalp dokularındaki iyon kanalı gen ifadelerindeki değişiklikler daha önce bildirilmemiştir. Araştırmamızda HHcy farelerinin beyin ve kalp dokularındaki 36 iyon kanalının ekspresyonunu karakterize etmek için kontrol fareleri ile kıyasladık. C57BL/6 J. fareleri, her biri 15 hayvandan oluşan iki gruba ayrıldı: (1) kontrol ve (2) HHcy grubu. HHcy, metiyonin uygulamasıyla indüklendi. İyon kanallarının mRNA seviyeleri, qRT-PCR kullanılarak analiz edildi. HHcy'nin kalp ve beyin dokularındaki olumsuz yan etkilerini doğrulamak için TUNEL boyama ve MDA testi kullanıldı. RT-PCR sonuçlarına göre kontrol ile karşılaştırıldığında HHcy grubunun beyin dokularında Hcn4, Trpc3, Trpm2'nin ifadesinin arttığı ve Abbc8, Cacna1b, Cacna1c, Cacna1e, Cacna1h, Hcn1, Kcnc3, Kcnh7, Kcnj8, Trpc4, Trpc5, Trpc6, Trpm3, Trpm4, Trpv4, Trpv6'nın ifadesinin azaldığı belirlendi. Kalp dokularında iyon kanalı ifadelerinde artış tespit edilmedi ancak Accn1, Accn2, Accn3, Hcn1, Kcnc4 ve Trpv6 iyon kanallarının ifadesinin azaldığı bulundu. HHcy grubunun beyin ve kalp dokularında apoptozis ve MDA düzeyinin kontrole göre anlamlı olarak yüksek olduğu belirlendi. Kalp dokularıyla karşılaştırıldığında beyin dokuları, HHcy'li farelerde kontrole göre çok önemli ve çeşitli bir iyon kanalı gen ekspresyon paterni sergiler. İyon kanallarının HHcy'deki rollerinin açıklığa kavuşturulması, yeni terapötik stratejilerin geliştirilmesine ışık tutabilir ve sonuçta HHcy yan etkilerini iyileştirebilir.
Anahtar Kelimeler
Asit Duyarlı İyon Kanalları Geçici Reseptör Potansiyel Kanalları Hiperhomosisteinemi Kalsiyum Kanalları Potasyum Kanalları
Proje Numarası
TF.11.67
Kaynakça
- 1. Pan JA, Fan Y, Gandhirajan RK, et al. Hyperactivation of the mammalian degenerin MDEG promotes caspase-8 activation and apoptosis. J Biol Chem. 2013;288(1):2952-63.
- 2. Boldyrev A, Bryushkova E, Mashkina A, et al. Why is homocysteine toxic for the nervous and immune systems? Curr Aging Sci. 2013;6(1):29-36.
- 3. Catterall WA, Dib-Hajj S, Meisler MH, et al. Inherited neuronal ion channelopathies: new windows on complex neurological diseases. J Neurosci. 2008;12(28):11768-77.
- 4. McClenaghan C, Hanson A, Sala-Rabanal, et al. Cantu syndrome associated SUR2 (ABCC9) mutations in distinct structural domains result inKATP channel gain-of-function by differential mechanisms. J Biol Chem. 2018;6:2041-52.
- 5. Ertel EA, Campbell KP, Harpold MM, et al. Nomenclature of voltage-gated calcium channels. Neuron. 2000;25:533-5.
- 6. Wahl-Schott C and Biel M. HCN channels: structure, cellular regulation and physiological function. Cell Mol Life Sci. 2009;66:470-94.
- 7. Jenkinson DH. Potassium channels - multiplicity and challenges. Br J Pharmacol. 2006;147:63-7.
- 8. Morelli MB, Amantini C, Liberati S, et al. TRP channels: new potential therapeutic approaches in CNS neuropathies. CNS Neurol Disord Drug Targets. 2013;12(1):274-93.
- 9. Song YS, Rosenfeld ME. Methionine-induced hyperhomocysteinemia promotes superoxide anion generation and NFkappaB activation in peritoneal macrophages of C57BL/6 mice. J Med Food. 2004;7(2):229-34.
- 10. Liu D, Scholze A, Zhu Z, et al. Increased transient receptor potential channel TRPC3 expression in spontaneously hypertensive rats. Am J Hypertens. 2005;18:1503-7.
- 11. Yagi K. Lipid peroxides and related radicals in clinical medicineIn: Free radicals in diagnostic medicine. Armstrong D, ed New York, Plenum Pres. 1994;1-15.
- 12. Lipton SA, Kim WK, Choi YB, et al. Neurotoxicity associated with dual actions of homocysteine at the N-methyl-D-aspartate receptor. Proc Natl Acad Sci USA. 1997;27: 5923-8.
- 13. Kruman II, Culmsee C, Chan SL, et al. Homocysteine elicits a DNA damage response in neurons that promotes apoptosis and hypersensitivity to excitotoxicity. J Neurosci. 2000;15: 6920-6.
- 14. Miller BA. The role of TRP channels in oxidative stress-induced cell death. J Membr Biol. 2006;209:31-41.
- 15. Simon F, Leiva-Salcedo E, Armisén R, et al. Hydrogen peroxide removes TRPM4 current desensitization conferring increased vulnerability to necrotic cell death. J Biol Chem. 2010;285(26):37150-8.
- 16. Weekman EM, Woolums AE, Sudduth TL, et al. Hyperhomocysteinemia-induced gene expression changes in the cell types of the brain. ASN Neuro. 2017;9(6):1759091417742296.
- 17. Patterson S, Scullion SM, McCluskey JT, et al. Prolonged exposure to homocysteine results in diminished but reversible pancreatic beta-cell responsiveness to insulinotropic agents. Diabetes Metab Res Rev. 2007;4:324-34.
- 18. Scherer EB, Schmitz F, Vuaden FC, et al. Mild hyperhomocysteinemia alters extracellular adenine metabolism in rat brain. Neuroscience. 2012;223:28-34.
- 19. Ashcroft SJ, Ashcroft FM. Properties and functions of ATP-sensitive K-channels. Cell Signal. 1990;2:197–214.
- 20. Phelan KD, Shwe UT, Abramowitz J, et al. Canonical transient receptor channel 5 (TRPC5) and TRPC1/4 contribute to seizure and excitotoxicity by distinct cellular mechanisms. Mol Pharmacol. 2013;83:429-38.
- 21. Distrutti E and Mencarelli A. The methionine connection: homocysteine and hydroge sulfide exert opposite effects on hepatic microcirculation in rats. Hepatology. 2008;2:659-67.
- 22. Budni J, Freitas AE, Binfaré RW, et al. Role of potassium channels in the antidepressant-like effect of folic acid in the forced swimming test in mice. Pharmacol Biochem Behav. 2012;1:148-54.
- 23. Biel M, Wahl-Schott C, Michalakis S, et al. Hyperpolarization-activated cation channels: from genes to function. Physiol Rev. 2009;89:847–85.
- 24. Sohn JW. Ion channels in the central regulation of energy and glucose homeostasis. Front Neurosci. 2013;23:85.
- 25. Selvaraj S, Sun Y, Singh BB. TRPC channels and their implication in neurological diseases. CNS Neurol Disord Drug Targets. 2010;9:94-104.
- 26. Li H, Huang J, Du W, et al. TRPC6 inhibited NMDA receptor activities and protected neurons from ischemic excitotoxicity. J Neurochem. 2010;123:1010-8.
- 27. Roedding AS, Tong SY, Au-Yeung W, et al. Chronic oxidative stress modulates TRPC3 and TRPM2 channel expression and function in rat primary cortical neurons: relevance to the pathophysiology of bipolar disorder. Brain Res. 2013;23:16-27.
- 28. Lee CR, Machold RP, Witkovsky P, et al. TRPM2 channels are required for NMDA-induced burst firing and contribute to H(2)O(2)-dependent modulation in substantia nigra pars reticulata GABAergic neurons. J Neurosci. 2013;16:1157-68.
- 29. Gerzanich V, Woo SK, Vennekens R, et al. De novo expression of Trpm4 initiates secondary hemorrhage in spinal cord injury. Nat Med. 2009;2:185-91.
- 30. Baron A, Diochot S, Salinas M, et al. Venom toxins in the exploration of molecular, physiological and pathophysiological functions of acid-sensing ion channels Toxicon. 2013;1:187-204.
- 31. Gibbons DD, Kutschke WJ, Weiss RM, et al. Heart failure induces changes in acid-sensing ion channels in sensory neurons innervating skeletal muscle. J Physiol. 2015;20:4575-87.
- 32. Moshal KS, Metreveli N, Frank I, et al. Mitochondrial MMP activation, dysfunction and arrhythmogenesis in hyperhomocysteinemia. Curr Vasc Pharmacol. 2008;6:84-92.
- 33. Cheng CF, Chen IL, Cheng MH, et al. Acid-sensing ion channel 3, but not capsaicin receptor TRPV1, plays a protective role in isoproterenol-induced myocardial ischemia in mice. Circ J. 2011;75:174-8.
- 34. Richter TA, Dvoryanchikov GA, Roper SD, et al. Acid-sensing ion channel-2 is not necessary for sour taste in mice. J Neurosci. 2004;21:4088-91.
- 35. Le Bouter S, Demolombe S, Chambellan A, et al. Microarray analysis reveals complex remodeling of cardiac ion channel expression with altered thyroid status: relation to cellular and integrated electrophysiology. Circ Res. 2003;2:234-42.
- 36. Fenske S, Krause SC, Hassan SI, et al. Sick sinus syndrome in HCN1-deficient mice. Circulation. 2013;24:2585-94.
- 37. Grant AO. Cardiac Ion Channels. Circ Arrhythmia Electrophysiol. 2009;2:185-194.
Ayrıntılar
| Birincil Dil | İngilizce |
|---|---|
| Konular | Klinik Tıp Bilimleri (Diğer) |
| Bölüm | Araştırma Makalesi |
| Yazarlar | |
| Proje Numarası | TF.11.67 |
| Yayımlanma Tarihi | 30 Nisan 2024 |
| Gönderilme Tarihi | 21 Ağustos 2023 |
| Yayımlandığı Sayı | Yıl 2024 Cilt: 11 Sayı: 1 |
