Mst1 regulates post-infarction cardiac injury through the JNK-Drp1-mitochondrial fission pathway

• Autorzy: Wang X. , Song Q.
• Języki publikacji: EN

Abstrakty

EN

Background: Post-infarction cardiac injury is closely associated with cardiac remodeling and heart dysfunction. Mammalian STE20-like kinase 1 (Mst1), a regulator of cellular apoptosis, is involved in cardiac remodeling in post-infarction heart, but the mechanisms remain poorly defined. We aimed to explore the role of Mst1 in regulating chronic post-infarction cardiac injury, with a focus on mitochondrial homoeostasis. Methods: Wild-type (WT) and Mst1-knockout mice were as the cardiac myocardial infarction model. Cardiac fibrosis, myocardial inflammation response, heart dysfunction and cardiomyocyte death were measured in vivo using immunohistochemistry, immunofluorescence, western blot, qPCR and TUNEL assays. Cardiomyocytes were isolated from WT and Mst1-knockout mice, and a chronic hypoxia model was used to induce damage. Mitochondrial function was determined via JC1 staining, ROS measurement, cyt-c leakage detection and mitochondrial apoptotic pathways analysis. Mitochondrial fission was observed using immunofluorescence. A pathway activator and inhibitor were applied to establish the signaling pathways involved in regulating mitochondrial homeostasis. Results: Our study demonstrated that Mst1 expression was significantly upregulated in the heart post-infarction. Activated Mst1 induced cardiac fibrosis, an excessive inflammatory response, and cardiomyocyte death, whereas the genetic ablation of Mst1 protected the myocardium against chronic post-infarction injury. Function assays showed that upregulation of Mst1 activity contributed to JNK pathway activation, which led to Drp1 migration from the cytoplasm onto the surface of the mitochondria, indicative of mitochondrial fission activation. Excessive mitochondrial fission caused mitochondrial fragmentation, resulting in mitochondrial potential collapse, ROS overproduction, mitochondrial pro-apoptotic leakage into the cytoplasm, and the initiation of caspase-9-mediated mitochondrial apoptosis. By contrast, Mst1 deletion helped to maintain mitochondrial structure and function, sending pro-survival signals to the cardiomyocytes. Conclusions: Our results identify Mst1 as a malefactor in the development of post-infarction cardiac injury and that it acts through the JNK-Drp1-mitochondrial fission pathway.

• Wydawca: -
• Czasopismo: Cellular and Molecular Biology Letters
• Rocznik: 2018
• Tom: 23
• Opis fizyczny: p.1-17,fig.,ref.

Twórcy

autor

Wang X.

• Department of Critical Care Medicine, the Chinese PLA General Hospital, Beijing, China

autor

Song Q.

• Department of Critical Care Medicine, the Chinese PLA General Hospital, Beijing, China

Bibliografia

• 1. Hu SY, Zhang Y, Zhu PJ, Zhou H, Chen YD. Liraglutide directly protects cardiomyocytes against reperfusion injury possibly via modulation of intracellular calcium homeostasis. J Geriatr Cardiol. 2017;14:57–66.
• 2. Zhou H, Yang J, Xin T, Zhang T, Hu S, Zhou S, Chen G, Chen Y. Exendin-4 enhances the migration of adiposederived stem cells to neonatal rat ventricular cardiomyocyte-derived conditioned medium via the phosphoinositide 3-kinase/Akt-stromal cell-derived factor-1alpha/CXC chemokine receptor 4 pathway. Mol Med Rep. 2015;11:4063–72.
• 3. Qiao H, Ren H, Du H, Zhang M, Xiong X, Lv R. Liraglutide repairs the infarcted heart: the role of the SIRT1/Parkin/ mitophagy pathway. Mol Med Rep. 2018;17:3722–34.
• 4. Pei HF, Hou JN, Wei FP, Xue Q, Zhang F, Peng CF, Yang Y, Tian Y, Feng J, Du J, He L, Li XC, Gao EH, Li, Yang YJ. Melatonin attenuates postmyocardial infarction injury via increasing Tom70 expression. J Pineal Res. 2017;62: e12371.
• 5. Zhou H, Zhu P, Guo J, Hu N, Wang S, Li D, Hu S, Ren J, Cao F, Chen Y. Ripk3 induces mitochondrial apoptosis via inhibition of FUNDC1 mitophagy in cardiac IR injury. Redox Biol. 2017;13:498–507.
• 6. Zhou H, Zhang Y, Hu S, Shi C, Zhu P, Ma Q, Jin Q, Cao F, Tian F, Chen Y. Melatonin protects cardiac microvasculature against ischemia/reperfusion injury via suppression of mitochondrial fission-VDAC1-HK2-mPTPmitophagy axis. J Pineal Res. 2017;63:e12413.
• 7. Zhou H, Li D, Zhu P, Hu S, Hu N, Ma S, Zhang Y, Han T, Ren J, Cao F, Chen Y. Melatonin suppresses platelet activation and function against cardiac ischemia/reperfusion injury via PPARgamma/FUNDC1/mitophagy pathways. J Pineal Res. 2017;63:e12438.
• 8. Dominguez-Rodriguez A, Abreu-Gonzalez P, De La Torre-Hernandez JM, Gonzalez-Gonzalez J, Garcia-Camarero T, Consuegra-Sanchez L, Garcia-Saiz MD, Aldea-Perona A, Virgos-Aller T, Azpeitia A, Reiter RJ, Investigators M. Effect of intravenous and intracoronary melatonin as an adjunct to primary percutaneous coronary intervention for acute ST-elevation myocardial infarction: results of the melatonin adjunct in the acute myocaRdial infarction treated with angioplasty trial. J Pineal Res. 2017;62:e12374.
• 9. Yu L, Fan C, Li Z, Zhang J, Xue X, Xu Y, Zhao G, Yang Y, Wang H. Melatonin rescues cardiac thioredoxin system during ischemia-reperfusion injury in acute hyperglycemic state by restoring Notch1/Hes1/Akt signaling in a membrane receptor-dependent manner. J Pineal Res. 2017;62:e12375.
• 10. Zhou H, Wang S, Zhu P, Hu S, Chen Y, Ren J. Empagliflozin rescues diabetic myocardial microvascular injury via AMPK-mediated inhibition of mitochondrial fission. Redox Biol. 2017;15:335–46.
• 11. Zhou H, Yang J, Xin T, Li D, Guo J, Hu S, Zhou S, Zhang T, Zhang Y, Han T, Chen Y. Exendin-4 protects adiposederived mesenchymal stem cells from apoptosis induced by hydrogen peroxide through the PI3K/Akt-Sfrp2 pathways. Free Radic Biol Med. 2014;77:363–75.
• 12. Zhang Y, Zhou H, Wu W, Shi C, Hu S, Yin T, Ma Q, Han T, Zhang Y, Tian F, Chen Y. Liraglutide protects cardiac microvascular endothelial cells against hypoxia/reoxygenation injury through the suppression of the SR-ca(2 +)-XO-ROS axis via activation of the GLP-1R/PI3K/Akt/survivin pathways. Free Radic Biol Med. 2016;95:278–92.
• 13. Zhu H, Jin Q, Li Y, Ma Q, Wang J, Li D, Zhou H, Chen Y. Melatonin protected cardiac microvascular endothelial cells against oxidative stress injury via suppression of IP3R-[ca(2+)]c/VDAC-[ca(2+)]m axis by activation of MAPK/ ERK signaling pathway. Cell Stress Chaperones. 2018;23:101–13.
• 14. Zhang W, Tao A, Lan T, Cepinskas G, Kao R, Martin CM, Rui T. Carbon monoxide releasing molecule-3 improves myocardial function in mice with sepsis by inhibiting NLRP3 inflammasome activation in cardiac fibroblasts. Basic Res Cardiol. 2017;112:16.
• 15. Zhou H, Hu S, Jin Q, Shi C, Zhang Y, Zhu P, Ma Q, Tian F, Chen Y. Mff-Dependent mitochondrial fission contributes to the pathogenesis of cardiac microvasculature ischemia/reperfusion injury via induction of mROSmediated Cardiolipin oxidation and HK2/VDAC1 disassociation-involved mPTP opening. J Am Heart Assoc. 2017;6: e005328.
• 16. Jin Q, Li R, Hu N, Xin T, Zhu P, Hu S, Ma S, Zhu H, Ren J, Zhou H. DUSP1 alleviates cardiac ischemia/reperfusion injury by suppressing the Mff-required mitochondrial fission and Bnip3-related mitophagy via the JNK pathways. Redox Biol. 2018;14:576–87.
• 17. Torres-Estay V, Carreno DV, Fuenzalida P, Watts A, San Francisco IF, Montecinos VP, Sotomayor PC, Ebos J, Smith GJ, Godoy AS. Androgens modulate male-derived endothelial cell homeostasis using androgen receptordependent and receptor-independent mechanisms. Angiogenesis. 2017;20:25–38.
• 18. Zhou H, Du W, Li Y, Shi C, Hu N, Ma S, Wang W, Ren J. Effects of melatonin on fatty liver disease: the role of NR4A1/DNA-PKcs/p53 pathway, mitochondrial fission, and mitophagy. J Pineal Res. 2018;64:e12450.
• 19. Shi C, Cai Y, Li Y, Li Y, Hu N, Ma S, Hu S, Zhu P, Wang W, Zhou H. Yap promotes hepatocellular carcinoma metastasis and mobilization via governing cofilin/F-actin/lamellipodium axis by regulation of JNK/Bnip3/SERCA/ CaMKII pathways. Redox Biol. 2018;14:59–71.
• 20. Li Q, Qi F, Meng X, Zhu C, Gao Y. Mst1 regulates colorectal cancer stress response via inhibiting Bnip3-related mitophagy by activation of JNK/p53 pathway. Cell Biol Toxicol. 2017. https://doi.org/10.1007/s10565-017-9417-6.
• 21. Zhang M, Zhang L, Hu J, Lin J, Wang T, Duan Y, Man W, Feng J, Sun L, Jia H, Li C, Zhang R, Wang H, Sun D. MST1 coordinately regulates autophagy and apoptosis in diabetic cardiomyopathy in mice. Diabetologia. 2016;59:2435–47.
• 22. Hu J, Zhang L, Yang Y, Guo Y, Fan Y, Zhang M, Man W, Gao E, Hu W, Reiter RJ, Wang H, Sun D. Melatonin alleviates postinfarction cardiac remodeling and dysfunction by inhibiting Mst1. J Pineal Res. 2017;62:e12368.
• 23. Garcia-Nino WR, Correa F, Rodriguez-Barrena JI, Leon-Contreras JC, Buelna-Chontal M, Soria-Castro E, HernandezPando R, Pedraza-Chaverri J, Zazueta C. Cardioprotective kinase signaling to subsarcolemmal and interfibrillar mitochondria is mediated by caveolar structures. Basic Res Cardiol. 2017;112:15.
• 24. Alghanem AF, Wilkinson EL, Emmett MS, Aljasir MA, Holmes K, Rothermel BA, Simms VA, Heath VL, Cross MJ. RCAN1.4 regulates VEGFR-2 internalisation, cell polarity and migration in human microvascular endothelial cells. Angiogenesis. 2017;20:341–58.
• 25. Zhou W, Yu L, Fan J, Wan B, Jiang T, Yin J, Huang Y, Li Q, Yin G, Hu Z. Endogenous parathyroid hormone promotes fracture healing by increasing expression of BMPR2 through cAMP/PKA/CREB pathway in mice. Cell Physiol Biochem. 2017;42:551–63.
• 26. Choi SI, Lee E, Akuzum B, Jeong JB, Maeng YS, Kim TI, Kim EK. Melatonin reduces endoplasmic reticulum stress and corneal dystrophy-associated TGFBIp through activation of endoplasmic reticulum-associated protein degradation. J Pineal Res. 2017;63:e12426.
• 27. Lee HJ, Jung YH, Choi GE, Ko SH, Lee SJ, Lee SH, Han HJ. BNIP3 induction by hypoxia stimulates FASN-dependent free fatty acid production enhancing therapeutic potential of umbilical cord blood-derived human mesenchymal stem cells. Redox Biol. 2017;13:426–43.
• 28. Li J, Chen L, Xiong Y, Zheng X, Xie Q, Zhou Q, Shi L, Wu C, Jiang J, Wang H. Knockdown of PD-L1 in human gastric Cancer cells inhibits tumor progression and improves the cytotoxic sensitivity to CIK therapy. Cell Physiol Biochem. 2017;41:907–20.
• 29. Couto JA, Ayturk UM, Konczyk DJ, Goss JA, Huang AY, Hann S, Reeve JL, Liang MG, Bischoff J, Warman ML, Greene AKA. Somatic GNA11 mutation is associated with extremity capillary malformation and overgrowth. Angiogenesis. 2017;20:303–6.
• 30. Jovancevic N, Dendorfer A, Matzkies M, Kovarova M, Heckmann JC, Osterloh M, Boehm M, Weber L, Nguemo F, Semmler J, Hescheler J, Milting H, Schleicher E, Gelis L, Hatt H. Medium-chain fatty acids modulate myocardial function via a cardiac odorant receptor. Basic Res Cardiol. 2017;112:13.
• 31. Le Cras TD, Mobberley-Schuman PS, Broering M, Fei L, Trenor CC 3rd, Adams DM. Angiopoietins as serum biomarkers for lymphatic anomalies. Angiogenesis. 2017;20:163–73.
• 32. Iggena D, Winter Y, Steiner B. Melatonin restores hippocampal neural precursor cell proliferation and prevents cognitive deficits induced by jet lag simulation in adult mice. J Pineal Res. 2017;62:e12397.
• 33. Zhou H, Li D, Shi C, Xin T, Yang J, Zhou Y, Hu S, Tian F, Wang J, Chen Y. Effects of Exendin-4 on bone marrow mesenchymal stem cell proliferation, migration and apoptosis in vitro. Sci Rep. 2015;5:12898.
• 34. Gao Y, Xiao X, Zhang C, Yu W, Guo W, Zhang Z, Li Z, Feng X, Hao J, Zhang K, Xiao B, Chen M, Huang W, Xiong S, Wu X, Deng W. Melatonin synergizes the chemotherapeutic effect of 5-fluorouracil in colon cancer by suppressing PI3K/AKT and NF-kappaB/iNOS signaling pathways. J Pineal Res. 2017;62:e12380.
• 35. Liu L, Li H, Cui Y, Li R, Meng F, Ye Z, Zhang X. Calcium Channel opening rather than the release of ATP causes the apoptosis of osteoblasts induced by overloaded mechanical stimulation. Cell Physiol Biochem. 2017;42:441–54.
• 36. Kalyanaraman B. Teaching the basics of cancer metabolism: developing antitumor strategies by exploiting the differences between normal and cancer cell metabolism. Redox Biol. 2017;12:833–42.
• 37. Das N, Mandala A, Naaz S, Giri S, Jain M, Bandyopadhyay D, Reiter RJ, Roy SS. Melatonin protects against lipidinduced mitochondrial dysfunction in hepatocytes and inhibits stellate cell activation during hepatic fibrosis in mice. J Pineal Res. 2017;62:e12404.
• 38. Han L, Wang H, Li L, Li X, Ge J, Reiter RJ, Wang Q. Melatonin protects against maternal obesity-associated oxidative stress and meiotic defects in oocytes via the SIRT3-SOD2-dependent pathway. J Pineal Res. 2017;63: e12404.
• 39. Xu J, Wu Y, Lu G, Xie S, Ma Z, Chen Z, Shen HM, Xia D. Importance of ROS-mediated autophagy in determining apoptotic cell death induced by physapubescin B. Redox Biol. 2017;12:198–207.
• 40. Liu Z, Gan L, Xu Y, Luo D, Ren Q, Wu S, Sun C. Melatonin alleviates inflammasome-induced pyroptosis through inhibiting NF-kappaB/GSDMD signal in mice adipose tissue. J Pineal Res. 2017;63:e12414.
• 41. Lefaki M, Papaevgeniou N, Chondrogianni N. Redox regulation of proteasome function. Redox Biol. 2017;13:452–8.
• 42. Zhai M, Li B, Duan W, Jing L, Zhang B, Zhang M, Yu L, Liu Z, Yu B, Ren K, Gao E, Yang Y, Liang H, Jin Z, Yu S. Melatonin ameliorates myocardial ischemia reperfusion injury through SIRT3-dependent regulation of oxidative stress and apoptosis. J Pineal Res. 2017;63:e12419.
• 43. Brasacchio D, Alsop AE, Noori T, Lufti M, Iyer S, Simpson KJ, Bird PI, Kluck RM, Johnstone RW, Trapani JA. Epigenetic control of mitochondrial cell death through PACS1-mediated regulation of BAX/BAK oligomerization. Cell Death Differ. 2017;24:961–70.
• 44. Pickard JM, Burke N, Davidson SM, Yellon DM. Intrinsic cardiac ganglia and acetylcholine are important in the mechanism of ischaemic preconditioning. Basic Res Cardiol. 2017;112:11.
• 45. Randriamboavonjy V, Kyselova A, Elgheznawy A, Zukunft S, Wittig I, Fleming I. Calpain 1 cleaves and inactivates prostacyclin synthase in mesenteric arteries from diabetic mice. Basic Res Cardiol. 2017;112:10.
• 46. Dufour F, Rattier T, Shirley S, Picarda G, Constantinescu AA, Morle A, Zakaria AB, Marcion G, Causse S, Szegezdi E, Zajonc DM, Seigneuric R, Guichard G, Gharbi T, Picaud F, Herlem G, Garrido C, Schneider P, Benedict CA, Micheau O. N-glycosylation of mouse TRAIL-R and human TRAIL-R1 enhances TRAIL-induced death. Cell Death Differ. 2017; 24:500–10.
• 47. Banerjee K, Keasey MP, Razskazovskiy V, Visavadiya NP, Jia C, Hagg T. Reduced FAK-STAT3 signaling contributes to ER stress-induced mitochondrial dysfunction and death in endothelial cells. Cell Signal. 2017;36:154–62.
• 48. Nunez-Gomez E, Pericacho M, Ollauri-Ibanez C, Bernabeu C, Lopez-Novoa JM. The role of endoglin in postischemic revascularization. Angiogenesis. 2017;20:1–24.
• 49. Wang N, Liu H, Li X, Zhang Q, Chen M, Jin Y, Deng X. Activities of MSCs derived from transgenic mice seeded on ADM scaffolds in wound healing and assessment by advanced optical techniques. Cell Physiol Biochem. 2017;42:623–39.
• 50. Oanh NTK, Park YY, Cho H. Mitochondria elongation is mediated through SIRT1-mediated MFN1 stabilization. Cell Signal. 2017;38:67–75.
• 51. Zhou H, Zhu P, Wang J, Zhu H, Ren J, Chen Y. Pathogenesis of cardiac ischemia reperfusion injury is associated with CK2alpha-disturbed mitochondrial homeostasis via suppression of FUNDC1-related mitophagy. Cell Death Differ. 2018. https://doi.org/10.1038/s41418-018-0086-7.
• 52. Zhou H, Yue Y, Wang J, Ma Q, Chen Y. Melatonin therapy for diabetic cardiomyopathy: a mechanism involving Syk-mitochondrial complex I-SERCA pathway. Cell Signal. 2018;47:88-100.
• 53. Ronchi C, Torre E, Rizzetto R, Bernardi J, Rocchetti M, Zaza A. Late sodium current and intracellular ionic homeostasis in acute ischemia. Basic Res Cardiol. 2017;112:12.
• 54. Ligeza J, Marona P, Gach N, Lipert B, Miekus K, Wilk W, Jaszczynski J, Stelmach A, Loboda A, Dulak J, Branicki W, Rys J, Jura J. MCPIP1 contributes to clear cell renal cell carcinomas development. Angiogenesis. 2017;20:325–40.
• 55. Zhou H, Shi C, Hu S, Zhu H, Ren J, Chen Y. BI1 is associated with microvascular protection in cardiac ischemia reperfusion injury via repressing Syk-Nox2-Drp1-mitochondrial fission pathways. Angiogenesis. 2018. https://doi. org/10.1007/s10456-018-9611-z.
• 56. Van Nostrand JL, Bowen ME, Vogel H, Barna M, Attardi LD. The p53 family members have distinct roles during mammalian embryonic development. Cell Death Differ. 2017;24:575–9.
• 57. O'mealey GB, Berry WL, Plafker SM. Sulforaphane is a Nrf2-independent inhibitor of mitochondrial fission. Redox Biol. 2017;11:103–10.
• 58. Zhou H, Wang J, Zhu P, Hu S, Ren J. Ripk3 regulates cardiac microvascular reperfusion injury: the role of IP3Rdependent calcium overload, XO-mediated oxidative stress and F-action/filopodia-based cellular migration. Cell Signal. 2018;45:12–22.
• 59. Yang HH, Chen Y, Gao CY, Cui ZT, Yao JM. Protective effects of MicroRNA-126 on human cardiac microvascular endothelial cells against hypoxia/Reoxygenation-induced injury and inflammatory response by activating PI3K/ Akt/eNOS signaling pathway. Cell Physiol Biochem. 2017;42:506–18.
• 60. Zhou H, Ma Q, Zhu P, Ren J, Reiter RJ, Chen Y. Protective role of melatonin in cardiac ischemia-reperfusion injury: from pathogenesis to targeted therapy. J Pineal Res. 2018;64:e12471.
• 61. Schock SN, Chandra NV, Sun Y, Irie T, Kitagawa Y, Gotoh B, Coscoy L, Winoto A. Induction of necroptotic cell death by viral activation of the RIG-I or STING pathway. Cell Death Differ. 2017;24:615–25.

Identyfikatory

DOI

10.1186/s11658-018-0085-1