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PLOS ONE  2013 

MicroRNA-1 Downregulation Increases Connexin 43 Displacement and Induces Ventricular Tachyarrhythmias in Rodent Hypertrophic Hearts

DOI: 10.1371/journal.pone.0070158

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Abstract:

Downregulation of the muscle-specific microRNA-1 (miR-1) mediates the induction of pathologic cardiac hypertrophy. Dysfunction of the gap junction protein connexin 43 (Cx43), an established miR-1 target, during cardiac hypertrophy leads to ventricular tachyarrhythmias (VT). However, it is still unknown whether miR-1 and Cx43 are interconnected in the pro-arrhythmic context of hypertrophy. Thus, in this study we investigated whether a reduction in the extent of cardiac hypertrophy could limit the pathological electrical remodeling of Cx43 and the onset of VT by modulating miR-1 levels. Wistar male rats underwent mechanical constriction of the ascending aorta to induce pathologic left ventricular hypertrophy (LVH) and afterwards were randomly assigned to receive 10mg/kg valsartan, VAL (LVH+VAL) delivered in the drinking water or placebo (LVH) for 12 weeks. Sham surgery was performed for control groups. Programmed ventricular stimulation reproducibly induced VT in LVH compared to LVH+VAL group. When compared to sham controls, rats from LVH group showed a significant decrease of miR-1 and an increase of Cx43 expression and its ERK1/2-dependent phosphorylation, which displaces Cx43 from the gap junction. Interestingly, VAL administration to rats with aortic banding significantly reduced cardiac hypertrophy and prevented miR-1 down-regulation and Cx43 up-regulation and phosphorylation. Gain- and loss-of-function experiments in neonatal cardiomyocytes (NCMs) in vitro confirmed that Cx43 is a direct target of miR-1. Accordingly, in vitro angiotensin II stimulation reduced miR-1 levels and increased Cx43 expression and phosphorylation compared to un-stimulated NCMs. Finally, in vivo miR-1 cardiac overexpression by an adenoviral vector intra-myocardial injection reduced Cx43 expression and phosphorylation in mice with isoproterenol-induced LVH. In conclusion, miR-1 regulates Cx43 expression and activity in hypertrophic cardiomyocytes in vitro and in vivo. Treatment of pressure overload-induced myocyte hypertrophy reduces the risk of life-threatening VT by normalizing miR-1 expression levels with the consequent stabilization of Cx43 expression and activity within the gap junction.

References

[1]  Levy D, Garrison RJ, Savage DD, Kannel WB, Castelli WP (1990) Prognostic implications of echocardiographically determined left ventricular mass in the Framingham Heart Study. N Engl J Med 322: 1561-1566. doi:10.1056/NEJM199005313222203. PubMed: 2139921.
[2]  Frey N, Katus HA, Olson EN, Hill JA (2004) Hypertrophy of the heart: a new therapeutic target? Circulation 109: 1580-1589. doi:10.1161/01.CIR.0000120390.68287.BB. PubMed: 15066961.
[3]  McLenachan JM, Henderson E, Morris KI, Dargie HJ (1987) Ventricular arrhythmias in patients with hypertensive left ventricular hypertrophy. N Engl J Med 317: 787-792. doi:10.1056/NEJM198709243171302. PubMed: 2957590.
[4]  Kozhevnikov DO, Yamamoto K, Robotis D, Restivo M, El-Sherif N (2002) Electrophysiological mechanism of enhanced susceptibility of hypertrophied heart to acquired torsade de pointes arrhythmias: tridimensional mapping of activation and recovery patterns. Circulation 105: 1128-1134. doi:10.1161/hc0902.104711. PubMed: 11877367.
[5]  Saffitz JE, Schuessler RB, Yamada KA (1999) Mechanisms of remodeling of gap junction distributions and the development of anatomic substrates of arrhythmias. Cardiovasc Res 42: 309-317. doi:10.1016/S0008-6363(99)00023-1. PubMed: 10533569.
[6]  Hunter JJ, Chien KR (1999) Signaling pathways for cardiac hypertrophy and failure. N Engl J Med 341: 1276-1283. doi:10.1056/NEJM199910213411706. PubMed: 10528039.
[7]  Pourdjabbar A, Parker TG, Nguyen QT, Desjardins JF, Lapointe N et al. (2005) Effects of pre-, peri-, and postmyocardial infarction treatment with losartan in rats: effect of dose on survival, ventricular arrhythmias, function, and remodeling. Am J Physiol Heart Circ Physiol 288: H1997-H2005. PubMed: 15539424.
[8]  Sovari AA, Iravanian S, Dolmatova E, Jiao Z, Liu H et al. (2011) Inhibition of c-Src tyrosine kinase prevents angiotensin II-mediated connexin-43 remodeling and sudden cardiac death. J Am Coll Cardiol 58: 2332-2339. PubMed: 22093512.
[9]  Ripplinger CM, Li W, Hadley J, Chen J, Rothenberg F et al. (2007) Enhanced transmural fiber rotation and Connexin 43 heterogeneity are associated with an increased upper limit of vulnerability in a transgenic rabbit model of human hypertrophic cardiomyopathy. Circ Res 101: 1049-1057. doi:10.1161/CIRCRESAHA.107.161240. PubMed: 17885214.
[10]  Kostin S, Dammer S, Hein S, Klovekorn WP, Bauer EP et al. (2004) Connexin 43 expression and distribution in compensated and decompensated cardiac hypertrophy in patients with aortic stenosis. Cardiovasc Res 62: 426-436. doi:10.1016/j.cardiores.2003.12.010. PubMed: 15094362.
[11]  Carè A, Catalucci D, Felicetti F, Bonci D, Addario A et al. (2007) MicroRNA-133 controls cardiac hypertrophy. Nat Med 13: 613-618. doi:10.1038/nm1582. PubMed: 17468766.
[12]  Mishima Y, Stahlhut C, Giraldez AJ (2007) miR-1-2 gets to the heart of the matter. Cell 129: 247-249. doi:10.1016/j.cell.2007.04.008. PubMed: 17448987.
[13]  Torella D, Iaconetti C, Catalucci D, Ellison GM, Leone A et al. (2011) MicroRNA-133 controls vascular smooth muscle cell phenotypic switch in vitro and vascular remodeling in vivo. Circ Res 109: 880-893. doi:10.1161/CIRCRESAHA.111.240150. PubMed: 21852550.
[14]  Ambros V (2004) The functions of animal microRNAs. Nature 431: 350-355. doi:10.1038/nature02871. PubMed: 15372042.
[15]  Belevych AE, Sansom SE, Terentyeva R, Ho HT, Nishijima Y et al. (2011) MicroRNA-1 and -133 increase arrhythmogenesis in heart failure by dissociating phosphatase activity from RyR2 complex. PLOS ONE 6(12): e28324. doi:10.1371/journal.pone.0028324. PubMed: 22163007.
[16]  Terentyev D, Belevych AE, Terentyeva R, Martin MM, Malana GE et al. (2009) miR-1 overexpression enhances Ca(2+) release and promotes cardiac arrhythmogenesis by targeting PP2A regulatory subunit B56alpha and causing CaMKII-dependent hyperphosphorylation of RyR2. Circ Res 104: 514-521. doi:10.1161/CIRCRESAHA.108.181651. PubMed: 19131648.
[17]  Zhao Y, Ransom JF, Li A, Vedantham V, von Drehle M et al. (2007) Dysregulation of cardiogenesis, cardiac conduction, and cell cycle in mice lacking miRNA-1-2. Cell 129: 303-317. doi:10.1016/j.cell.2007.03.030. PubMed: 17397913.
[18]  Iaconetti C, Polimeni A, Sorrentino S, Sabatino J, Pironti G et al. (2012) Inhibition of miR-92a increases endothelial proliferation and migration in vitro as well as reduces neointimal proliferation in vivo after vascular injury. Basic Res Cardiol 107: 296-310. doi:10.1007/s00395-012-0296-y. PubMed: 22890560.
[19]  House SL, House BE, Glascock B, Kimball T, Nusayr E et al. (2010) Fibroblast growth factor 2 mediates isoproterenol-induced cardiac hypertrophy through activation of the extracellular regulated kinase. Mol Cell Pharmacol 2: 143-154. PubMed: 21274419.
[20]  Indolfi C, Di Lorenzo E, Perrino C, Stingone AM, Curcio A et al. (2002) Hydroxymethylglutaryl coenzyme A reductase inhibitor simvastatin prevents cardiac hypertrophy induced by pressure overload and inhibits p21ras activation. Circulation 106: 2118-2124. doi:10.1161/01.CIR.0000034047.70205.97. PubMed: 12379583.
[21]  Yoo B, Lemaire A, Mangmool S, Wolf MJ, Curcio A et al. (2009) Beta1-adrenergic receptors stimulate cardiac contractility and CaMKII activation in vivo and enhance cardiac dysfunction following myocardial infarction. Am J Physiol Heart Circ Physiol 297: H1377-H1386. doi:10.1152/ajpheart.00504.2009. PubMed: 19633206.
[22]  Curcio A, Noma T, Naga Prasad SV, Wolf MJ, Lemaire A et al. (2006) Competitive displacement of phosphoinositide 3-kinase from beta-adrenergic receptor kinase-1 improves postinfarction adverse myocardial remodeling. Am J Physiol Heart Circ Physiol 291: H1754-H1760. doi:10.1152/ajpheart.01199.2005. PubMed: 16699071.
[23]  Chin BB, Metzler SD, Lemaire A, Curcio A, Vemulapalli S et al. (2007) Left ventricular functional assessment in mice: feasibility of high spatial and temporal resolution ECG-gated blood pool SPECT. Radiology 245: 440-448. doi:10.1148/radiol.2452061973. PubMed: 17940303.
[24]  Huang C, Bao M, Jiang H, Liu J, Yang B et al. (2004) Differences in the changing trends of monophasic action potential duration and effective refractory period of the ventricular myocardium after myocardial infarction in vivo. Circ J 68: 1205-1209. doi:10.1253/circj.68.1205. PubMed: 15564708.
[25]  Torella D, Gasparri C, Ellison GM, Curcio A, Leone A et al. (2009) Differential regulation of vascular smooth muscle and endothelial cell proliferation in vitro and in vivo by cAMP/PKA-activated p85alphaPI3K. Am J Physiol Heart Circ Physiol 297: H2015-H2025. doi:10.1152/ajpheart.00738.2009. PubMed: 19783773.
[26]  Ellison GM, Torella D, Dellegrottaglie S, Perez-Martinez C, Perez de Prado A et al. (2011) Endogenous cardiac stem cell activation by insulin-like growth factor-1/hepatocyte growth factor intracoronary injection fosters survival and regeneration of the infarcted pig heart. J Am Coll Cardiol 58: 977-986. doi:10.1016/j.jacc.2011.05.013. PubMed: 21723061.
[27]  Curcio A, Torella D, Cuda G, Coppola C, Faniello MC et al. (2004) Effect of stent coating alone on in vitro vascular smooth muscle cell proliferation and apoptosis. Am J Physiol Heart Circ Physiol 286: H902-H908. PubMed: 14592937.
[28]  Horita S, Zheng Y, Hara C, Yamada H, Kunimi M et al. (2002) Biphasic regulation of Na+-HCO3- cotransporter by angiotensin II type 1A receptor. Hypertension 40: 707-712. doi:10.1161/01.HYP.0000036449.70110.DE. PubMed: 12411466.
[29]  Lu Y, Zhang Y, Shan H, Pan Z, Li X et al. (2009) MicroRNA-1 downregulation by propranolol in a rat model of myocardial infarction: a new mechanism for ischaemic cardioprotection. Cardiovasc Res 84: 434-441. doi:10.1093/cvr/cvp232. PubMed: 19581315.
[30]  Ma TK, Kam KK, Yan BP, Lam YY (2010) Renin-angiotensin-aldosterone system blockade for cardiovascular diseases: current status. Br J Pharmacol 160: 1273-1292. doi:10.1111/j.1476-5381.2010.00750.x. PubMed: 20590619.
[31]  Tsai CT, Wang DL, Chen WP, Hwang JJ, Hsieh CS et al. (2007) Angiotensin II increases expression of alpha1C subunit of L-type calcium channel through a reactive oxygen species and cAMP response element-binding protein-dependent pathway in HL-1 myocytes. Circ Res 100: 1476-1485. doi:10.1161/01.RES.0000268497.93085.e1. PubMed: 17463319.
[32]  Lampe PD, Lau AF (2000) Regulation of gap junctions by phosphorylation of connexins. Arch Biochem Biophys 384: 205-215. doi:10.1006/abbi.2000.2131. PubMed: 11368307.
[33]  Solan JL, Lampe PD (2009) Connexin43 phosphorylation: Structural changes and biological effects. Biochem J 419: 261-272. doi:10.1042/BJ20082319. PubMed: 19309313.
[34]  Yang B, Lin H, Xiao J, Lu Y, Luo X et al. (2007) The muscle-specific microRNA miR-1 regulates cardiac arrhythmogenic potential by targeting GJA1 and KCNJ2. Nat Med 13: 486-491. doi:10.1038/nm1569. PubMed: 17401374.
[35]  Ikeda S, He A, Kong SW, Lu J, Bejar R et al. (2009) MicroRNA-1 negatively regulates expression of the hypertrophy-associated calmodulin and Mef2a genes. Mol Cell Biol 29: 2193-2204. doi:10.1128/MCB.01222-08. PubMed: 19188439.
[36]  Fedele M, Fidanza V, Battista S, Pentimalli F, Klein-Szanto AJ et al. (2006) Haploinsufficiency of the Hmga1 gene causes cardiac hypertrophy and myelo-lymphoproliferative disorders in mice. Cancer Res 66: 2536-2543. doi:10.1158/0008-5472.CAN-05-1889. PubMed: 16510570.
[37]  Vos MA, de Groot SH, Verduyn SC, van der Zande J, Leunissen HD et al. (1998) Enhanced susceptibility for acquired torsade de pointes arrhythmias in the dog with chronic, complete AV block is related to cardiac hypertrophy and electrical remodeling. Circulation 98: 1125-1135. doi:10.1161/01.CIR.98.11.1125. PubMed: 9736600.
[38]  Biagetti MO, Quinteiro RA (2006) Gender differences in electrical remodeling and susceptibility to ventricular arrhythmias in rabbits with left ventricular hypertrophy. Heart Rhythm 3: 832-839. doi:10.1016/j.hrthm.2006.03.010. PubMed: 16818217.
[39]  Fischer R, Dechend R, Gapelyuk A, Shagdarsuren E, Gruner K et al. (2007) Angiotensin II-induced sudden arrhythmic death and electrical remodeling. Am J Physiol Heart Circ Physiol 293: 1242-1253. doi:10.1152/ajpheart.01400.2006. PubMed: 17416596.
[40]  Ellison GM, Torella D, Karakikes I, Purushothaman S, Curcio A et al. (2007) Acute beta-adrenergic overload produces myocyte damage through calcium leakage from the ryanodine receptor 2 but spares cardiac stem cells. J Biol Chem 282: 11397-11409. doi:10.1074/jbc.M607391200. PubMed: 17237229.
[41]  Emdad L, Uzzaman M, Takagishi Y, Honjo H, Uchida T et al. (2001) Gap junction remodeling in hypertrophied left ventricles of aortic-banded rats: Prevention by angiotensin II type 1 receptor blockade. J Mol Cell Cardiol 33: 219-231. doi:10.1006/jmcc.2000.1293. PubMed: 11162128.
[42]  Ek-Vitorin JF, King TJ, Heyman NS, Lampe PD, Burt JM (2006) Selectivity of Connexin 43 channels is regulated through protein kinase C-dependent phosphorylation. Circ Res 98: 1498-1505. doi:10.1161/01.RES.0000227572.45891.2c. PubMed: 16709897.
[43]  Warn-Cramer BJ, Cottrell GT, Burt JM, Lau AF (1998) Regulation of connexin-43 gap junctional intercellular communication by mitogen-activated protein kinase. J Biol Chem 273: 9188-9196. doi:10.1074/jbc.273.15.9188. PubMed: 9535909.
[44]  Cottrell GT, Lin R, Warn-Cramer BJ, Lau AF, Burt JM (2003) Mechanism of v-Src- and mitogen-activated protein kinase-induced reduction of gap junction communication. Am J Physiol Cell Physiol 284: C511-C520. doi:10.1152/ajpcell.00214.2002. PubMed: 12388103.
[45]  Pahujaa M, Anikin M, Goldberg GS (2007) Phosphorylation of connexin43 induced by Src: Regulation of gap junctional communication between transformed cells. Exp Cell Res 313: 4083-4090. doi:10.1016/j.yexcr.2007.09.010. PubMed: 17956757.
[46]  Indolfi C, Gasparri C, Vicinanza C, De Serio D, Boncompagni D et al. (2011) Mitogen-activated protein kinases activation in T lymphocytes of patients with acute coronary syndromes. Basic Res Cardiol 106: 667-679. doi:10.1007/s00395-011-0172-1. PubMed: 21424618.
[47]  Torella D, Curcio A, Gasparri C, Galuppo V, De Serio D et al. (2007) Fludarabine prevents smooth muscle proliferation in vitro and neointimal hyperplasia in vivo through specific inhibition of STAT-1 activation. Am J Physiol Heart Circ Physiol 292: H2935-H2943. doi:10.1152/ajpheart.00887.2006. PubMed: 17293493.
[48]  Laurila JP, Castellone MD, Curcio A, Laatikainen LE, Haaparanta-Solin M et al. (2009) Extracellular superoxide dismutase is a growth regulatory mediator of tissue injury recovery. Mol Ther 17: 448-454. doi:10.1038/mt.2008.282. PubMed: 19107121.
[49]  Mongiardo A, Curcio A, Spaccarotella C, Parise S, Indolfi C (2004) Molecular mechanisms of restenosis after percutaneous peripheral angioplasty and approach to endovascular therapy. Curr Drug Targets Cardiovasc Haematol Disord 4: 275-287. doi:10.2174/1568006043336258. PubMed: 15379621.
[50]  Cohn JN, Tognoni G, Valsartan Heart Failure Trial Investigators (2001) A randomized trial of the angiotensin-receptor blocker valsartan in chronic heart failure. N Engl J Med 345: 1667-1675.
[51]  Elia L, Contu R, Quintavalle M, Varrone F, Chimenti C et al. (2009) Reciprocal regulation of microRNA-1 and insulin-like growth factor-1 signal transduction cascade in cardiac and skeletal muscle in physiological and pathological conditions. Circulation 120: 2377-2385. doi:10.1161/CIRCULATIONAHA.109.879429. PubMed: 19933931.
[52]  Liu N, Williams AH, Kim Y, McAnally J, Bezprozvannaya S et al. (2007) An intragenic MEF2-dependent enhancer directs muscle-specific expression of microRNAs 1 and 133. Proc Natl Acad Sci U S A 104: 20844-20849. doi:10.1073/pnas.0710558105. PubMed: 18093911.
[53]  Karakikes I, Chaanine AH, Kang S, Mukete BN, Jeong D et al. (2013) Therapeutic cardiac-targeted delivery of miR-1 reverses pressure overload-induced cardiac hypertrophy and attenuates pathological remodeling. J AM Heart Assoc, 2: e000078. doi:10.1161/JAHA.113.000078. PubMed: 23612897. PubMed: 23612897.
[54]  Condorelli G, Drusco A, Stassi G, Roncarati R, Iaccarino G et al. (2002) Akt induces enhanced myocardial contractility and cell size in vivo in transgenic mice. Proc Natl Acad Sci U S A 99: 12333-12338. doi:10.1073/pnas.172376399. PubMed: 12237475.
[55]  Ellison GM, Waring CD, Vicinanza C, Torella D (2012) Physiological cardiac remodelling in response to endurance exercise training: cellular and molecular mechanisms. Heart 98: 5-10. doi:10.1136/heartjnl-2012-301877b.3. PubMed: 21880653.
[56]  Shiojima I, Sato K, Izumiya Y, Schiekofer S, Ito M et al. (2005) Disruption of coordinated cardiac hypertrophy and angiogenesis contributes to the transition to heart failure. J Clin Invest 115: 2108-2118. doi:10.1172/JCI24682. PubMed: 16075055.

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