mTOR'un inhibisyonu, MEK1/ERK1/2 etkinliğini düzenleyerek sıçanlarda arka bacak iskemi-reperfüzyonunun neden olduğu iskelet kası ve böbrek zedelenmesine karşı koruma sağlar
Yıl 2022,
Cilt: 47 Sayı: 1, 219 - 232, 31.03.2022
Çağla Akıncı Uysal
Meryem Temiz Reşitoğlu
,
Demet Sinem Güden
,
Sefika Pınar Şenol
,
Özden Vezir
,
Nehir Sucu
,
Bahar Tunçtan
Kafait U. Malik
Seyhan Fırat
Öz
Amaç: Arka bacak iskemisi/reperfüzyonun (İ/R) sıçan modellerinde, rapamisinin memelilerdeki hedefi (mTOR)/inhibitör-κB-α/nükleer faktör-κB p65 sinyal ileti yolu etkinliğinin, artan oksidatif/nitrozatif stres ve inflamatuvar yanıt yoluyla organ zedelenmelerine aracılık ettiğini daha önce göstermiştik. mTOR’un İ/R zedelenmesine katkıda bulunduğuna ilişkin önceki bulgularımızı referans alarak, bu çalışmada arka bacak İ/R'ye bağlı hedef ve uzak organ zedelenmelerinde mTOR ile MEK1/ERK1/2 yolu arasındaki olası etkileşime odaklanmayı amaçladık.
Gereç ve Yöntem: Erkek Wistar sıçanlar dört gruba ayrıldı. Arka bacak İ/R, her iki arka ekstremitelerine turnikeler uygulanarak iskemi oluşturuldu. İskemiden 4 saat sonra turnikeler açılarak 4 saat reperfüzyon uygulandı. 4 saatlik reperfüzyondan sonra kan, böbrek ve gastroknemius kası izole edildi.
Bulgular: Arka bacak İ/R uygulaması gastroknemius kasında, böbrekte ve/veya serumda rpS6, MEK1, ERK1/2, tümör nekroz faktörü-α, indüklenebilir nitrik oksit sentaz, gp91phox, p22phox ve nitrotirozinin fosforilasyonu ve/veya ekspresyonu ile birlikte nitrit düzeylerinde artışa neden oldu. Ayrıca, İ/R uygulanan sıçanların dokularında nikotinamit adenin dinükleotit fosfat oksidaz ve miyeloperoksidaz seviyeleri arttı. mTOR'un seçici inhibitörü olan rapamisin, sıçanlarda kas ve böbrek dokusunda İ/R'nin neden olduğu yukarıda bahsedilen tüm etkileri ortadan kaldırdı.
Sonuç: Bu veriler, MEK1/ERK1/2 yolunun etkinliğinin, mTOR’un aracılık ettiği arka bacak İ/R’nin neden olduğu hedef ve uzak organ zedelenmesine katkıda bulunduğunu göstermektedir.
Destekleyen Kurum
Mersin Üniversitesi
Proje Numarası
2018-2-TP2-2984
Kaynakça
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- Grace PA. Ischaemia-reperfusion injury. Br J Surg. 1994;81:637-47.
- Yassin MM, Harkin DW, Barros D’Sa AA, Halliday MI, Rowlands BJ. Lower limb ischemiaereperfusion injury triggers a systemic inflammatory response and multiple organ dysfunction. World J Surg. 2002;26:115-21.
- Tassiopoulos AK, Carlin RE, Gao Y, Pedoto A, Finck CM, Landas SK et al. Role of nitric oxide and tumor necrosis factor on lung injury caused by ischemia/reperfusion of the lower extremities. J Vasc Surg. 1997;26:647-56.
- Blaisdell FW. The pathophysiology of skeletal muscle ischemia and the reperfusion syndrome: a review. Cardiovasc Surg. 2002;10:620-30.
- Acar RD, Sahin M, Kirma C. One of the most urgent vascular circumstances: Acute limb ischemia. SAGE Open Med. 2013;1:2050312113516110.
- Volanska M, Zavacky P, Bober J. Ischaemic-reperfusion damage of tissue and critical limb ischaemia. Bratisl Lek Listy. 2006;107:264-8.
- Takhtfooladi MA, Jahanshahi G, Jahanshahi A, Sotoudeh A, Samiee Amlashi O, Allahverdi A. Effects of N-acetylcysteine on liver remote injury after skeletal muscle ischemia reperfusion in rats. Turk J Gastroenterol. 2014;25:43-7.
- Takhtfooladi MA, Jahanshahi A, Sotoudeh A, Jahanshahi G, Takhtfooladi HA, Aslani K. Effect of tramadol on lung injury induced by skeletal muscle ischemia reperfusion: an experimental study. J Bras Pneumol. 2013;39:434-9.
- Takhtfooladi MA, Takhtfooladi HA, Moayer F, Karimi P, Asl HA. Effect of Otostegia persica extraction on renal injury induced by hindlimb ischemia-reperfusion: a rat model. Int J Surg. 2015;13:124-30.
- Takhtfooladi MA, Jahanshahi A, Sotoudeh A, Daneshi MH, Khansari M, Takhtfooladi HA. The antioxidant role of N-acetylcysteine on the testicular remote injury after skeletal muscle ischemia and reperfusion in rats. Pol J Pathol. 2013;64:204-9.
- Emrecan B, Tulukoglu E, Bozok S, Kestelli M, Onem G, Küpelioglu A et al. Effects of iloprost and pentoxifylline on renal ischemia-reperfusion in rabbit model. Eur J Med Res. 2006;11:295-9.
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- Li X, Ren C, Li S, Han R, Gao J, Huang Q et al. Limb remote ischemic conditioning promotes myelination by upregulating PTEN/Akt/ mTOR signaling activities after chronic cerebral hypoperfusion. Aging Dis. 2017;8:392-401.
- Javedan G, Shidfar F, Davoodi SH, Ajami M, Gorjipour F, Sureda A et al. Conjugated linoleic acid rat
pretreatment reduces renal damage in ischemia/reperfusion injury: Unraveling antiapoptotic mechanisms and regulation of phosphorylated mammalian target of rapamycin. Mol Nutr Food Res. 2016;60:2665-77.
- Pazoki-Toroudi H, Nilforoushzadeh MA, Ajami M, Jaffary F, Aboutaleb N, Nassiri-Kashani M et al. Combination of azelaic acid 5% and clindamycin 2% for the treatment of acne vulgaris. Cutan Ocul Toxicol. 2011;30:286-91.
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- Sucu N, Unlu A, Tamer L, Aytacoğlu B, Coskun B, Bilgin R et al. Effects of trimetazidine on tissue damage in kidney after hindlimb ischemia-reperfusion. Pharmacol Res. 2002;46:345-9.
- Temiz-Resitoglu M, Kucukkavruk SP, Guden DS, Cecen P, Sari AN, Tunctan B et al. Activation of mTOR/IκB-α/NF-κB pathway contributes to LPS-induced hypotension and inflammation in rats. Eur J Pharmacol. 2017;802:7-19.
- Tunctan B, Korkmaz B, Sari AN, Kacan M, Unsal D, Serin MS et al. Contribution of iNOS/sGC/PKG pathway, COX-2, CYP4A1, and gp91phox to The protective effect of 5,14-HEDGE, a20-HETE mimetic, against vasodilation, hypotension, tachycardia, and inflammation in a rat model of septic shock. Nitric Oxide. 2013a;33:18-41.
- Tunctan B, Korkmaz B, Sari AN, Kacan M, Unsal D, Serin MS et al. 5,14-HEDGE, a 20-HETE mimetic, reverses hypotension and improves survival in a rodent model of septic shock: contribution of soluble epoxide hydrolase, CYP2C23, MEK1/ERK1/2/IKKβ/IκB-α/NF-κB pathway, and proinflammatory cytokine formation. Prostaglandins Other Lipid Mediat. 2013b;102-103:31-41.
- Sahan-Firat S, Temiz-Resitoglu M, Guden DS, Kucukkavruk SP, Tunctan B, Sari AN et al. Protection by mTOR inhibition on zymosan-induced systemic inflammatory response and oxidative/nitrosative stress: Contribution of mTOR/MEK1/ERK1/2/IKKβ/IκB-α/NF-κB signalling pathway. Inflammation. 2018;41:276-98.
- Green LC, Wagner DA, Glogowski J, Skipper PL, Wishnok JS, Tannenbaum SR. Analysis of nitrate, nitrite, and [15N] nitrate in biological fluids. Anal Biochem. 1982;126:131-8.
- Raedschelders K, Ansley DM, Chen DD. The cellular and molecular origin of reactive oxygen species generation during myocardial ischemia and reperfusion. Pharmacol Ther. 2012;133:230-55.
- Crozier SJ, Zhang X, Wang J, Cheung J, Kimball SR, Jefferson LS. Activation of signaling pathways and regulatory mechanisms of mRNA translation following myocardial ischemia-reperfusion. J Appl Physiol. 2006;101:576-82.
- Foster KG, Fingar DC. Mammalian target of rapamycin (mTOR): conducting the cellular signaling symphony. J Biol Chem. 2010;285:14071-7.
- Sofer A, Lei K, Johannessen CM, Ellisen LW. Regulation of mTOR and cell growth in response to energy stress by REDD1. Mol Cell Biol. 2005;25:5834-45.
- Koh PO. Gingko biloba extract (EGb 761) prevents cerebral ischemia-induced p70S6 kinase and S6 phosphorylation. Am J Chin Med. 2010;38:727-34.
- Yang X, Hei C, Liu P, Song Y, Thomas T, Tshimanga S et al. Inhibition of mTOR pathway by rapamycin reduces brain damage in rats subjected to transient forebrain ischemia. Int J Biol Sci. 2015;11:1424-35.
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Inhibition of mTOR protects against skeletal muscle and kidney injury following hindlimb ischemia-reperfusion in rats by regulating MEK1/ERK1/2 activity
Yıl 2022,
Cilt: 47 Sayı: 1, 219 - 232, 31.03.2022
Çağla Akıncı Uysal
Meryem Temiz Reşitoğlu
,
Demet Sinem Güden
,
Sefika Pınar Şenol
,
Özden Vezir
,
Nehir Sucu
,
Bahar Tunçtan
Kafait U. Malik
Seyhan Fırat
Öz
Purpose: We have previously demonstrated that activation of the mammalian target of rapamycin (mTOR)/inhibitory-κB-α/nuclear factor-κB p65 signaling pathway mediates organ injuries through increased oxidative/nitrosative stress and inflammatory response in rat models of hind limb ischemia/reperfusion (HL I/R). Following up our previous findings regarding I/R injury through mammalian target of rapamycin (mTOR), we aimed to focus on the possible interaction between mammalian target of rapamycin (mTOR and mitogen-activated protein kinase kinase (MEK)1/extracellular signal-regulated kinase (ERK) 1/2 pathway in hind limb ischemia/reperfusion (HL I/R) resulting in target and remote organ injuries in the present study.
Materials and Methods: Male Wistar rats were divided into four groups. HL I/R was induced by occluding with tourniquets of both hind limbs. Following 4 h, the tourniquets were removed following reperfusion for 4 h. After 4 h of reperfusion blood, kidney, and gastrocnemius muscle were collected.
Results: HL I/R caused an increase in phosphorylation and/or expression of rpS6, MEK1, ERK1/2, tumor necrosis factor-α, inducible nitric oxide synthase, gp91phox, p22phox, and nitrotyrosine as well as nitrite levels in gastrocnemius muscle, kidney, and/or serum. Additionally, nicotinamide adenine dinucleotide phosphate oxidase and myeloperoxidase levels were increased in the tissues of rats subjected to HL I/R. Rapamycin, the selective inhibitor of mTOR, abolished all the effects mentioned above caused by HL I/R in the rat’s muscle and kidney.
Conclusion: These data suggest that activation of the MEK1/ERK1/2 pathway contributes to mTOR-mediated HL I/R-induced target and remote organ injury.
Proje Numarası
2018-2-TP2-2984
Kaynakça
- Land WG. The role of postischemic reperfusion injury and other nonantigen-dependent inflammatory pathways in transplantation. Transplantation. 2005;79:505-14.
- Grace PA. Ischaemia-reperfusion injury. Br J Surg. 1994;81:637-47.
- Yassin MM, Harkin DW, Barros D’Sa AA, Halliday MI, Rowlands BJ. Lower limb ischemiaereperfusion injury triggers a systemic inflammatory response and multiple organ dysfunction. World J Surg. 2002;26:115-21.
- Tassiopoulos AK, Carlin RE, Gao Y, Pedoto A, Finck CM, Landas SK et al. Role of nitric oxide and tumor necrosis factor on lung injury caused by ischemia/reperfusion of the lower extremities. J Vasc Surg. 1997;26:647-56.
- Blaisdell FW. The pathophysiology of skeletal muscle ischemia and the reperfusion syndrome: a review. Cardiovasc Surg. 2002;10:620-30.
- Acar RD, Sahin M, Kirma C. One of the most urgent vascular circumstances: Acute limb ischemia. SAGE Open Med. 2013;1:2050312113516110.
- Volanska M, Zavacky P, Bober J. Ischaemic-reperfusion damage of tissue and critical limb ischaemia. Bratisl Lek Listy. 2006;107:264-8.
- Takhtfooladi MA, Jahanshahi G, Jahanshahi A, Sotoudeh A, Samiee Amlashi O, Allahverdi A. Effects of N-acetylcysteine on liver remote injury after skeletal muscle ischemia reperfusion in rats. Turk J Gastroenterol. 2014;25:43-7.
- Takhtfooladi MA, Jahanshahi A, Sotoudeh A, Jahanshahi G, Takhtfooladi HA, Aslani K. Effect of tramadol on lung injury induced by skeletal muscle ischemia reperfusion: an experimental study. J Bras Pneumol. 2013;39:434-9.
- Takhtfooladi MA, Takhtfooladi HA, Moayer F, Karimi P, Asl HA. Effect of Otostegia persica extraction on renal injury induced by hindlimb ischemia-reperfusion: a rat model. Int J Surg. 2015;13:124-30.
- Takhtfooladi MA, Jahanshahi A, Sotoudeh A, Daneshi MH, Khansari M, Takhtfooladi HA. The antioxidant role of N-acetylcysteine on the testicular remote injury after skeletal muscle ischemia and reperfusion in rats. Pol J Pathol. 2013;64:204-9.
- Emrecan B, Tulukoglu E, Bozok S, Kestelli M, Onem G, Küpelioglu A et al. Effects of iloprost and pentoxifylline on renal ischemia-reperfusion in rabbit model. Eur J Med Res. 2006;11:295-9.
- Gradl G, Gaida S, Finke B, Lindenblatt N, Gierer P, Menger MD et al. Supernatant of traumatized muscle induces inflammation and pain, but not microcirculatory perfusion failure and apoptotic cell death. Shock. 2005;24:219-25.
- Hsu KY, Chen C, Shih P, Huang C. Adverse effects of bilateral lower limb ischemiaereperfusion on inducing kidney injuries in rats could be ameliorated by platonin. Acta Anaesthesiol Taiwan. 2012;50:63-8.
- Li X, Ren C, Li S, Han R, Gao J, Huang Q et al. Limb remote ischemic conditioning promotes myelination by upregulating PTEN/Akt/ mTOR signaling activities after chronic cerebral hypoperfusion. Aging Dis. 2017;8:392-401.
- Javedan G, Shidfar F, Davoodi SH, Ajami M, Gorjipour F, Sureda A et al. Conjugated linoleic acid rat
pretreatment reduces renal damage in ischemia/reperfusion injury: Unraveling antiapoptotic mechanisms and regulation of phosphorylated mammalian target of rapamycin. Mol Nutr Food Res. 2016;60:2665-77.
- Pazoki-Toroudi H, Nilforoushzadeh MA, Ajami M, Jaffary F, Aboutaleb N, Nassiri-Kashani M et al. Combination of azelaic acid 5% and clindamycin 2% for the treatment of acne vulgaris. Cutan Ocul Toxicol. 2011;30:286-91.
- Chen HC, Fong TH, Hsu PW, Chiu WT. Multifaceted effects of rapamycin on functional recovery after spinal cord injury in rats through autophagy promotion, anti-inflammation and neuroprotection. J Surg Res. 2013;179:203-10.
- Fletcher L, Evans TM, Watts LT, Jimenez DF, Digicaylioglu M. Rapamycin treatment improves neuron viability in an in vitro model of stroke. PLoS One. 2013;8:e68281.
- Liang D, Han D, Fan W, Zhang R, Qiao H, Fan M et al. Therapeutic efficacy of apelin on transplanted mesenchymal stem cells in hindlimb ischemic mice via regulation of autophagy. Sci Rep. 2016;6:21914.
- Zhao D, Yang J. Insights for oxidative stress and mTOR signaling in myocardial ischemia/reperfusion injury under diabetes. Oxid Med Cell Longev. 2017;6437467.
- Wei H, Li Y, Han S, Liu S, Zhang N, Zhao L et al. cPKCgamma-modulated autophagy in neurons alleviates ischemic ınjury in brain of mice with ischemic stroke through Akt-mTOR pathway. Transl Stroke Res. 2016;7:497-511.
- Kocak Z, Temiz-Resitoglu M, Guden DS, Vezir O, Sucu N, Balcı S et al. Modulation of oxidative-nitrosative stress and inflammatory response by rapamycin in target and distant organs in rats exposed to hindlimb ischemia-reperfusion: the role of mammalian target of rapamycin. Can J Physiol Pharmacol. 2019;97:1193-203.
- Sari AN, Kacan M, Unsal D, Sahan-Firat S, Buharalioglu CK, Vezir O et al. Contribution of RhoA/Rho-kinase/MEK1/ERK1/2/iNOS pathway to ischemia/reperfusion-induced oxidative/nitrosative stress and inflammation leading to distant and target organ injury in rats. Eur J Pharmacol. 2014;723:234-45.
- Sucu N, Unlu A, Tamer L, Aytacoğlu B, Coskun B, Bilgin R et al. Effects of trimetazidine on tissue damage in kidney after hindlimb ischemia-reperfusion. Pharmacol Res. 2002;46:345-9.
- Temiz-Resitoglu M, Kucukkavruk SP, Guden DS, Cecen P, Sari AN, Tunctan B et al. Activation of mTOR/IκB-α/NF-κB pathway contributes to LPS-induced hypotension and inflammation in rats. Eur J Pharmacol. 2017;802:7-19.
- Tunctan B, Korkmaz B, Sari AN, Kacan M, Unsal D, Serin MS et al. Contribution of iNOS/sGC/PKG pathway, COX-2, CYP4A1, and gp91phox to The protective effect of 5,14-HEDGE, a20-HETE mimetic, against vasodilation, hypotension, tachycardia, and inflammation in a rat model of septic shock. Nitric Oxide. 2013a;33:18-41.
- Tunctan B, Korkmaz B, Sari AN, Kacan M, Unsal D, Serin MS et al. 5,14-HEDGE, a 20-HETE mimetic, reverses hypotension and improves survival in a rodent model of septic shock: contribution of soluble epoxide hydrolase, CYP2C23, MEK1/ERK1/2/IKKβ/IκB-α/NF-κB pathway, and proinflammatory cytokine formation. Prostaglandins Other Lipid Mediat. 2013b;102-103:31-41.
- Sahan-Firat S, Temiz-Resitoglu M, Guden DS, Kucukkavruk SP, Tunctan B, Sari AN et al. Protection by mTOR inhibition on zymosan-induced systemic inflammatory response and oxidative/nitrosative stress: Contribution of mTOR/MEK1/ERK1/2/IKKβ/IκB-α/NF-κB signalling pathway. Inflammation. 2018;41:276-98.
- Green LC, Wagner DA, Glogowski J, Skipper PL, Wishnok JS, Tannenbaum SR. Analysis of nitrate, nitrite, and [15N] nitrate in biological fluids. Anal Biochem. 1982;126:131-8.
- Raedschelders K, Ansley DM, Chen DD. The cellular and molecular origin of reactive oxygen species generation during myocardial ischemia and reperfusion. Pharmacol Ther. 2012;133:230-55.
- Crozier SJ, Zhang X, Wang J, Cheung J, Kimball SR, Jefferson LS. Activation of signaling pathways and regulatory mechanisms of mRNA translation following myocardial ischemia-reperfusion. J Appl Physiol. 2006;101:576-82.
- Foster KG, Fingar DC. Mammalian target of rapamycin (mTOR): conducting the cellular signaling symphony. J Biol Chem. 2010;285:14071-7.
- Sofer A, Lei K, Johannessen CM, Ellisen LW. Regulation of mTOR and cell growth in response to energy stress by REDD1. Mol Cell Biol. 2005;25:5834-45.
- Koh PO. Gingko biloba extract (EGb 761) prevents cerebral ischemia-induced p70S6 kinase and S6 phosphorylation. Am J Chin Med. 2010;38:727-34.
- Yang X, Hei C, Liu P, Song Y, Thomas T, Tshimanga S et al. Inhibition of mTOR pathway by rapamycin reduces brain damage in rats subjected to transient forebrain ischemia. Int J Biol Sci. 2015;11:1424-35.
- Fan W, Han D, Sun Z, Ma S, Gao L, Chen J et al. Endothelial deletion of mTORC1 protects against hindlimb ischemia in diabetic mice via activation of autophagy, attenuation of oxidative stress and alleviation of inflammation. Free Radic Biol Med. 2017;108:725-40.
- Roux PP, Blenis J. ERK and p38 MAPK-activated protein kinases: a family of protein kinases with diverse biological functions. Microbiol Mol Biol Rev. 2004;68:320-44.
- Carletti R, Tacconi S, Bettini E, Ferraguiti F. Stress activated protein kinases, a novel family of mitogen-activated protein kinases are heterogeneously expressed in the adult rat brain and differentially disturbed extracellular-signal-regulated protein kinases. Neuroscience. 1995;69:1103-10.
- Duan W, Chan JH, Wong CH, Leung BP, Wong WS. Anti-inflammatory effects of mitogen-activated protein kinase kinase inhibitor U0126 in an asthma mouse model. J Immunol. 2004;172:7053-9.
- Lee PJ, Zhang X, Shan P, Ma B, Lee CG, Homer RJ. ERK1/2 mitogen-activated protein kinase selectively mediates IL-13-induced lung inflammation and remodeling in vivo. J Clin Invest. 2006;116:163-73.
- Wang ZQ, Wu DC, Huang FP, Yang GY. Inhibition of MEK/ERK 1/2 pathway reduces proinflammatory cytokine interleukin-1 expression in focal cerebral ischemia. Brain Res. 2004;996:55-66.
- Alessandrini A, Namura S, Moskowitz MA, Bonventre JV. MEK1 protein kinase inhibition protects against damage resulting from focal cerebral ischemia. Proc Natl Acad Sci USA. 1999;96:12866-9.
- Namura S, Iihara K, Takami S, Nagata I, Kikuchi H, Matsushita K et al. Intravenous administration of MEK inhibitor U0126 affords brain protection against forebrain ischemia and focal cerebral ischemia. Proc Natl Acad Sci USA. 2001;98:11569-74.
- Vinten-Johansen J. Involvement of neutrophils in the pathogenesis of lethal myocardial reperfusion injury. Cardiovasc Res. 2004;61:481-97.
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