Top

Published in:

01-08-2017 | Original Article

MiR-126 Affects Brain-Heart Interaction after Cerebral Ischemic Stroke

Authors: Jieli Chen, Chengcheng Cui, Xiaoping Yang, Jiang Xu, Poornima Venkat, Alex Zacharek, Peng Yu, Michael Chopp

Published in: Translational Stroke Research | Issue 4/2017

Abstract

Cardiovascular diseases are approximately three times higher in patients with neurological deficits than in patients without neurological deficits. MicroRNA-126 (MiR-126) facilitates vascular remodeling and decreases fibrosis and is emerging as an important factor in the pathogenesis of cardiovascular diseases and cerebral stroke. In this study, we tested the hypothesis that decreased miR-126 after ischemic stroke may play an important role in regulating cardiac function. Wild-type (WT), specific conditional-knockout endothelial cell miR-126 (miR-126^EC−/−), and miR-126 knockout control (miR-126^fl/fl) mice were subjected to distal middle cerebral artery occlusion (dMCAo) (n = 10/group). Cardiac hemodynamics and function were measured using transthoracic Doppler echocardiography. Mice were sacrificed at 28 days after dMCAo. WT mice subjected to stroke exhibited significantly decreased cardiac ejection fraction and increased myocyte hypertrophy, fibrosis as well as increased heart inflammation, infiltrating macrophages, and oxidative stress compared to non-stroke animals. Stroke significantly decreased serum and heart miR-126 expression and increased miR-126 target genes, vascular cell adhesion protein-1, and monocyte chemotactic protein-1 gene, and protein expression in the heart compared to non-stroke mice. MiR-126^EC−/− mice exhibited significantly decreased cardiac function and increased cardiomyocyte hypertrophy, fibrosis, and inflammatory factor expression after stroke compared to miR-126^fl/fl stroke mice. Exosomes derived from endothelial cells of miR-126^EC−/− (miR-126^EC−/−EC-Exo) mice exhibited significantly decreased miR-126 expression than exosomes derived from miR-126^fl/fl (miR-126^fl/fl-EC-Exo) mice. Treatment of cardiomyocytes subjected to oxygen glucose deprivation with miR-126^fl/fl-EC-Exo exhibited significantly decreased hypertrophy than with miR-126^EC−/−EC-Exo treatment. Ischemic stroke directly induces cardiac dysfunction. Decreasing miR-126 expression may contribute to cardiac dysfunction after stroke in mice.

Koh SH, Park HH. Neurogenesis in stroke recovery. Transl Stroke Res. 2016; doi:10.1007/s12975-016-0460-z.PubMed

Cassidy JM, Cramer SC. Spontaneous and therapeutic-induced mechanisms of functional recovery after stroke. Transl Stroke Res. 2016; doi:10.1007/s12975-016-0467-5.PubMed

Wira 3rd CR, Rivers E, Martinez-Capolino C, Silver B, Iyer G, Sherwin R, et al. Cardiac complications in acute ischemic stroke. The Western Journal of Emergency Medicine. 2011;12(4):414–20. doi:10.5811/westjem.2011.2.1765.CrossRefPubMedPubMedCentral

Imam YZ, D’Souza A, Malik RA, Shuaib A. Secondary stroke prevention: improving diagnosis and management with newer technologies. Transl Stroke Res. 2016;7(6):458–77. doi:10.1007/s12975-016-0494-2.CrossRefPubMed

Ergul A, Hafez S, Fouda A, Fagan SC. Impact of comorbidities on acute injury and recovery in preclinical stroke research: focus on hypertension and diabetes. Transl Stroke Res. 2016;7(4):248–60. doi:10.1007/s12975-016-0464-8.CrossRefPubMed

Ay H, Koroshetz WJ, Benner T, Vangel MG, Melinosky C, Arsava EM, et al. Neuroanatomic correlates of stroke-related myocardial injury. Neurology. 2006;66(9):1325–9. doi:10.1212/01.wnl.0000206077.13705.6d.CrossRefPubMed

Oppenheimer SM. Neurogenic cardiac effects of cerebrovascular disease. Curr Opin Neurol. 1994;7(1):20–4.CrossRefPubMed

Ishikawa H, Tajiri N, Vasconcellos J, Kaneko Y, Mimura O, Dezawa M, et al. Ischemic stroke brain sends indirect cell death signals to the heart. Stroke. 2013;44(11):3175–82. doi:10.1161/STROKEAHA.113.001714.CrossRefPubMed

Gongora-Rivera F, Labreuche J, Jaramillo A, Steg PG, Hauw JJ, Amarenco P. Autopsy prevalence of coronary atherosclerosis in patients with fatal stroke. Stroke. 2007;38(4):1203–10. doi:10.1161/01.str.0000260091.13729.96.CrossRefPubMed

10.

Tokgozoglu SL, Batur MK, Topcuoglu MA, Saribas O, Kes S, Oto A. Effects of stroke localization on cardiac autonomic balance and sudden death. Stroke. 1999;30(7):1307–11.CrossRefPubMed

11.

Swerdel JN, Janevic TM, Kostis WJ, Faiz A, Cosgrove NM, Kostis JB. Association between dehydration and short-term risk of ischemic stroke in patients with atrial fibrillation. Transl Stroke Res. 2016; doi:10.1007/s12975-016-0471-9.PubMed

12.

Oppenheimer SM, Gelb A, Girvin JP, Hachinski VC. Cardiovascular effects of human insular cortex stimulation. Neurology. 1992;42(9):1727–32.CrossRefPubMed

13.

Rosenzweig S, Carmichael ST. Age-dependent exacerbation of white matter stroke outcomes: a role for oxidative damage and inflammatory mediators. Stroke. 2013;44(9):2579–86. doi:10.1161/STROKEAHA.113.001796.CrossRefPubMedPubMedCentral

14.

Mishra PK, Tyagi N, Kumar M, Tyagi SC. MicroRNAs as a therapeutic target for cardiovascular diseases. J Cell Mol Med. 2009;13(4):778–89. doi:10.1111/j.1582-4934.2009.00744.x.CrossRefPubMedPubMedCentral

15.

Schober A, Nazari-Jahantigh M, Wei Y, Bidzhekov K, Gremse F, Grommes J, et al. MicroRNA-126-5p promotes endothelial proliferation and limits atherosclerosis by suppressing Dlk1. Nat Med. 2014;20(4):368–76. doi:10.1038/nm.3487.CrossRefPubMedPubMedCentral

16.

Hsu A, Chen SJ, Chang YS, Chen HC, Chu PH. Systemic approach to identify serum microRNAs as potential biomarkers for acute myocardial infarction. Biomed Res Int. 2014;2014:418628. doi:10.1155/2014/418628.PubMedPubMedCentral

17.

Long G, Wang F, Li H, Yin Z, Sandip C, Lou Y, et al. Circulating miR-30a, miR-126 and let-7b as biomarker for ischemic stroke in humans. BMC Neurol. 2013;13:178. doi:10.1186/1471-2377-13-178.CrossRefPubMedPubMedCentral

18.

Wei XJ, Han M, Yang FY, Wei GC, Liang ZG, Yao H, et al. Biological significance of miR-126 expression in atrial fibrillation and heart failure. Braz J Med Biol Res. 2015;48(11):983–9. doi:10.1590/1414-431X20154590.CrossRefPubMedPubMedCentral

19.

Kuraoka M, Furuta T, Matsuwaki T, Omatsu T, Ishii Y, Kyuwa S, et al. Direct experimental occlusion of the distal middle cerebral artery induces high reproducibility of brain ischemia in mice. Experimental animals/Japanese Association for Laboratory Animal Science. 2009;58(1):19–29.CrossRef

20.

Rosell A, Agin V, Rahman M, Morancho A, Ali C, Koistinaho J, et al. Distal occlusion of the middle cerebral artery in mice: are we ready to assess long-term functional outcome? Transl Stroke Res. 2013;4(3):297–307. doi:10.1007/s12975-012-0234-1.CrossRefPubMed

21.

Claxton S, Kostourou V, Jadeja S, Chambon P, Hodivala-Dilke K, Fruttiger M. Efficient, inducible Cre-recombinase activation in vascular endothelium. Genesis. 2008;46(2):74–80. doi:10.1002/dvg.20367.CrossRefPubMed

22.

Kuhnert F, Mancuso MR, Hampton J, Stankunas K, Asano T, Chen CZ, et al. Attribution of vascular phenotypes of the murine Egfl7 locus to the microRNA miR-126. Development. 2008;135(24):3989–93. doi:10.1242/dev.029736.CrossRefPubMed

23.

Yang XP, Liu YH, Rhaleb NE, Kurihara N, Kim HE, Carretero OA. Echocardiographic assessment of cardiac function in conscious and anesthetized mice. Am J Phys. 1999;277(5 Pt 2):H1967–74.

24.

Swanson RA, Morton MT, Tsao-Wu G, Savalos RA, Davidson C, Sharp FR. A semiautomated method for measuring brain infarct volume. J Cereb Blood Flow Metab. 1990;10(2):290–3.CrossRefPubMed

25.

Xu J, Carretero OA, Liao TD, Peng H, Shesely EG, Xu J, et al. Local angiotensin II aggravates cardiac remodeling in hypertension. Am J Physiol Heart Circ Physiol. 2010;299(5):H1328–38. doi:10.1152/ajpheart.00538.2010.CrossRefPubMedPubMedCentral

26.

Mito S, Ozono R, Oshima T, Yano Y, Watari Y, Yamamoto Y, et al. Myocardial protection against pressure overload in mice lacking Bach1, a transcriptional repressor of heme oxygenase-1. Hypertension. 2008;51(6):1570–7. doi:10.1161/HYPERTENSIONAHA.107.102566.CrossRefPubMed

27.

Belostotskaya GB, Golovanova TA. Characterization of contracting cardiomyocyte colonies in the primary culture of neonatal rat myocardial cells: a model of in vitro cardiomyogenesis. Cell Cycle. 2014;13(6):910–8. doi:10.4161/cc.27768.CrossRefPubMedPubMedCentral

28.

Cui X, Chopp M, Zacharek A, Ye X, Roberts C, Chen J. Angiopoietin-Tie2 pathway mediates type 2 diabetes induced vascular damage after cerebral stroke. Neurobiol Dis. 2011;43(1):285–92. doi:10.1016/j.nbd.2011.04.005.CrossRefPubMedPubMedCentral

29.

Xu J, Sun Y, Carretero OA, Zhu L, Harding P, Shesely EG, et al. Effects of cardiac overexpression of the angiotensin II type 2 receptor on remodeling and dysfunction in mice post-myocardial infarction. Hypertension. 2014;63(6):1251–9.CrossRefPubMedPubMedCentral

30.

Chen J, Ning R, Zacharek A, Cui C, Cui X, Yan T, et al. MiR-126 contributes to human umbilical cord blood cell induced Neurorestorative effects after stroke in type-2 diabetic mice. Stem Cells. 2015; doi:10.1002/stem.2193.

31.

Arner E, Mejhert N, Kulyte A, Balwierz PJ, Pachkov M, Cormont M, et al. Adipose tissue microRNAs as regulators of CCL2 production in human obesity. Diabetes. 2012;61(8):1986–93. doi:10.2337/db11-1508.CrossRefPubMedPubMedCentral

32.

Witkowski M, Weithauser A, Tabaraie T, Steffens D, Krankel N, Witkowski M, et al. Micro-RNA-126 reduces the blood thrombogenicity in diabetes mellitus via targeting of tissue factor. Arterioscler Thromb Vasc Biol. 2016; doi:10.1161/ATVBAHA.115.306094.PubMedPubMedCentral

33.

Harris TA, Yamakuchi M, Ferlito M, Mendell JT, Lowenstein CJ. MicroRNA-126 regulates endothelial expression of vascular cell adhesion molecule 1. Proc Natl Acad Sci U S A. 2008;105(5):1516–21. doi:10.1073/pnas.0707493105.CrossRefPubMedPubMedCentral

34.

Rauh R, Fischereder M, Spengel FA. Transesophageal echocardiography in patients with focal cerebral ischemia of unknown cause. Stroke. 1996;27(4):691–4.CrossRefPubMed

35.

Kim JM, Jung KH, Chu K, Lee ST, Ban J, Moon J, et al. Atherosclerosis-related circulating MicroRNAs as a predictor of stroke recurrence. Transl Stroke Res. 2015;6(3):191–7. doi:10.1007/s12975-015-0390-1.CrossRefPubMed

36.

Turchinovich A, Samatov TR, Tonevitsky AG, Burwinkel B. Circulating miRNAs: cell-cell communication function? Front Genet. 2013;4:119. doi:10.3389/fgene.2013.00119.CrossRefPubMedPubMedCentral

37.

Peng G, Yuan Y, Wu S, He F, Hu Y, Luo B. MicroRNA let-7e is a potential circulating biomarker of acute stage ischemic stroke. Transl Stroke Res. 2015;6(6):437–45. doi:10.1007/s12975-015-0422-x.CrossRefPubMed

38.

Small EM, Frost RJA, Olson EN. MicroRNAs add a new dimension to cardiovascular disease. Circulation. 2010;121(8):1022–32. doi:10.1161/CIRCULATIONAHA.109.889048.CrossRefPubMedPubMedCentral

39.

Fei L, Zhang J, Niu H, Yuan C, Ma X. Effects of rosuvastatin and MiR-126 on myocardial injury induced by acute myocardial infarction in rats: role of vascular endothelial growth factor a (VEGF-A). Medical Science Monitor: International Medical Journal of Experimental and Clinical Research. 2016;22:2324–34. doi:10.12659/MSM.896983.CrossRef

40.

Olivieri F, Spazzafumo L, Bonafe M, Recchioni R, Prattichizzo F, Marcheselli F, et al. MiR-21-5p and miR-126a-3p levels in plasma and circulating angiogenic cells: relationship with type 2 diabetes complications. Oncotarget. 2015;6(34):35372–82. doi:10.18632/oncotarget.6164.PubMedPubMedCentral

41.

Chen F, Du Y, Esposito E, Liu Y, Guo S, Wang X, et al. Effects of focal cerebral ischemia on exosomal versus serum miR126. Transl Stroke Res. 2015;6(6):478–84. doi:10.1007/s12975-015-0429-3.CrossRefPubMed

42.

Long G, Wang F, Duan Q, Chen F, Yang S, Gong W, et al. Human circulating microRNA-1 and microRNA-126 as potential novel indicators for acute myocardial infarction. Int J Biol Sci. 2012;8(6):811–8. doi:10.7150/ijbs.4439.CrossRefPubMedPubMedCentral

43.

Potus F, Ruffenach G, Dahou A, Thebault C, Breuils-Bonnet S, Tremblay E, et al. Downregulation of microRNA-126 contributes to the failing right ventricle in pulmonary arterial hypertension. Circulation. 2015;132(10):932–43. doi:10.1161/CIRCULATIONAHA.115.016382.CrossRefPubMed

44.

Silvani A, Calandra-Buonaura G, Dampney RA, Cortelli P. Brain-heart interactions: physiology and clinical implications. Philos Trans A Math Phys Eng Sci. 2016;374(2067) doi:10.1098/rsta.2015.0181.

45.

Daniele O, Caravaglios G, Fierro B, Natale E. Stroke and cardiac arrhythmias. J Stroke Cerebrovasc Dis. 2002;11(1):28–33. doi:10.1053/jscd.2002.123972.CrossRefPubMed

46.

Liesz A, Kleinschnitz C. Regulatory T cells in post-stroke immune homeostasis. Transl Stroke Res. 2016;7(4):313–21. doi:10.1007/s12975-016-0465-7.CrossRefPubMed

47.

Atangana E, Schneider UC, Blecharz K, Magrini S, Wagner J, Nieminen-Kelha M, et al. Intravascular inflammation triggers intracerebral activated microglia and contributes to secondary brain injury after experimental subarachnoid hemorrhage (eSAH). Transl Stroke Res. 2016; doi:10.1007/s12975-016-0485-3.PubMed

48.

Ahmad M, Graham SH. Inflammation after stroke: mechanisms and therapeutic approaches. Transl Stroke Res. 2010;1(2):74–84. doi:10.1007/s12975-010-0023-7.CrossRefPubMedPubMedCentral

49.

Yao Y, Tsirka SE. Chemokines and their receptors in intracerebral hemorrhage. Transl Stroke Res. 2012;3(1):70–9. doi:10.1007/s12975-012-0155-z.CrossRefPubMed

50.

Lambert JM, Lopez EF, Lindsey ML. Macrophage roles following myocardial infarction. Int J Cardiol. 2008;130(2):147–58. doi:10.1016/j.ijcard.2008.04.059.CrossRefPubMedPubMedCentral

51.

Mewhort HE, Lipon BD, Svystonyuk DA, Teng G, Guzzardi DG, Silva C, et al. Monocytes increase human cardiac myofibroblast-mediated extracellular matrix remodeling through TGF-beta1. Am J Physiol Heart Circ Physiol. 2016;310(6):H716–24. doi:10.1152/ajpheart.00309.2015.CrossRefPubMed

52.

Bujak M, Frangogiannis NG. The role of TGF-beta signaling in myocardial infarction and cardiac remodeling. Cardiovasc Res. 2007;74(2):184–95. doi:10.1016/j.cardiores.2006.10.002.CrossRefPubMed

53.

Liu Y, Zhang J. Nox2 contributes to cardiac fibrosis in diabetic cardiomyopathy in a transforming growth factor-beta dependent manner. Int J Clin Exp Pathol. 2015;8(9):10908–14.PubMedPubMedCentral

Title: MiR-126 Affects Brain-Heart Interaction after Cerebral Ischemic Stroke
Authors: Jieli Chen
Chengcheng Cui
Xiaoping Yang
Jiang Xu
Poornima Venkat
Alex Zacharek
Peng Yu
Michael Chopp
Publication date: 01-08-2017
Publisher: Springer US
Published in: Translational Stroke Research / Issue 4/2017
Print ISSN: 1868-4483
Electronic ISSN: 1868-601X
DOI: https://doi.org/10.1007/s12975-017-0520-z

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

MiR-126 Affects Brain-Heart Interaction after Cerebral Ischemic Stroke

Abstract

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 4/2017

Simvastatin Promotes Hematoma Absorption and Reduces Hydrocephalus Following Intraventricular Hemorrhage in Part by Upregulating CD36

Task-Specific Motor Rehabilitation Therapy After Stroke Improves Performance in a Different Motor Task: Translational Evidence

Evidence for Decreased Brain Parenchymal Volume After Large Intracerebral Hemorrhages: a Potential Mechanism Limiting Intracranial Pressure Rises

Translational Stroke Research Opportunities and a Strategy to Develop Effective Cytoprotection

Sodium Tanshinone IIA Sulfonate Enhances Effectiveness Rt-PA Treatment in Acute Ischemic Stroke Patients Associated with Ameliorating Blood-Brain Barrier Damage

Preclinical Development of a Prophylactic Neuroprotective Therapy for the Preventive Treatment of Anticipated Ischemia-Reperfusion Injury