Advanced SearchSearch Tips
miR-185 inhibits endoplasmic reticulum stress-induced apoptosis by targeting Na+/H+ exchanger-1 in the heart
facebook(new window)  Pirnt(new window) E-mail(new window) Excel Download
  • Journal title : BMB Reports
  • Volume 49, Issue 4,  2016, pp.208-213
  • Publisher : Korean Society for Biochemistry and Molecular Biology
  • DOI : 10.5483/BMBRep.2016.49.4.193
 Title & Authors
miR-185 inhibits endoplasmic reticulum stress-induced apoptosis by targeting Na+/H+ exchanger-1 in the heart
Kim, Jin Ock; Kwon, Eun Jeong; Song, Dong Woo; Lee, Jong Sub; Kim, Do Han;
  PDF(new window)
Prolonged ER stress (ERS) can be associated with the induction of apoptotic cell death in various heart diseases. In this study, we searched for microRNAs affecting ERS in the heart using in silico and in vitro methods. We found that miR-185 directly targets the 3′-untranslated region of Na+/H+ exchanger-1 (NHE-1), a protein involved in ERS. Cardiomyocyte ERS-triggered apoptosis induced by 100 ng/ml tunicamycin (TM) or 1 μM thapsigargin (TG), ERS inducers, was significantly reduced by miR-185 overexpression. Protein expression of pro-apoptotic markers such as CCAAT/enhancer-binding protein homologous protein (CHOP) and cleaved-caspase-3 was also markedly reduced by miR-185 in a dose-dependent manner. Cariporide (20 μM), a pharmacological inhibitor of NHE-1, also attenuated ERS-induced apoptosis in cardiomyocytes and CHOP protein expression, suggesting that NHE-1 plays an important role in ERS-associated apoptosis in cardiomyocytes. Collectively, the present results demonstrate that miR-185 is involved in cardio-protection against ERS-mediated apoptotic cell death.
Cariporide;Caspase-3;CHOP;microRNA;Unfolded protein response;
 Cited by
MicroRNA as a Therapeutic Target in Cardiac Remodeling, BioMed Research International, 2017, 2017, 2314-6141, 1  crossref(new windwow)
Ron D and Walter P (2007) Signal integration in the endoplasmic reticulum unfolded protein resonse. Nat Rev Mol Cell Biol 8, 519-529 crossref(new window)

Groenendyk J, Agellon LB and Michalak M (2013) Coping with endoplasmic reticulum stress in the cardiovascular system. Annu Rev Physiol 75, 49-67 crossref(new window)

Ryoo HD (2015) Drosophila as a model for unfolded protein response research. BMB Rep 48, 445-453 crossref(new window)

Arduíno DM, Raquel Esteves A, Filipa Domingues A et al (2009) ER-mediated stress induces mitochondrial-dependent caspases activation in NT2 neuron-like cells. BMB Rep 42, 719-724 crossref(new window)

Groenendyk J, Sreenivasaiah PK, Kim DH, Agellon LB and Michalak M (2010) Biology of endoplasmic reticulum stress in the heart. Circ Res 107, 1185-1197 crossref(new window)

Valencia-Sanchez MA, Liu J, Hannon GJ and Parker R (2006) Control of translation and mRNA degradation by miRNAs and siRNAs. Genes Dev 20, 515-524 crossref(new window)

Leite-Moreira AM, Lourenço AP, Falcão-Pires I and Leite-Moreira AF (2013) Pivotal role of microRNAs in cardiac physiology and heart failure. Drug Discov Today 18, 1243-1249 crossref(new window)

Varga Z V, Zvara A, Faragó N et al (2014) MicroRNAs associated with ischemia-reperfusion injury and cardioprotection by ischemic pre- and postconditioning: protectomiRs. Am J Physiol Heart Circ Physiol 307, H216-H227 crossref(new window)

He S, Liu P, Jian Z et al (2013) MiR-138 protects cardiomyocytes from hypoxia-induced apoptosis via MLK3/JNK/c-jun pathway. Biochem Biophys Res Commun 441, 763-769 crossref(new window)

Nakamura TY, Iwata Y, Arai Y, Komamura K and Wakabayashi S (2008) Activation of Na+/H+ exchanger 1 is sufficient to generate Ca2+ signals that induce cardiac hypertrophy and heart failure. Circ Res 103, 891-899 crossref(new window)

Chakrabarti S, Hoque AN and Karmazyn M (1997) A rapid ischemia-induced apoptosis in isolated rat hearts and its attenuation by the sodium-hydrogen exchange inhibitor HOE 642 (cariporide). J Mol Cell Cardiol 29, 3169-3174 crossref(new window)

Gumina RJ, Mizumura T, Beier N, Schelling P, Schultz JJ and Gross GJ (1998) A new sodium/hydrogen exchange inhibitor, EMD 85131, limits infarct size in dogs when administered before or after coronary artery occlusion. J Pharmacol Exp Ther 286, 175-183

Knight DR, Smith AH, Flynn DM et al (2001) A novel sodium-hydrogen exchanger isoform-1 inhibitor, zoniporide, reduces ischemic myocardial injury in vitro and in vivo. J Pharmacol Exp Ther 297, 254-259

Alvarez B V and Villa-Abrille MC (2013) Mitochondrial NHE1: a newly identified target to prevent heart disease. Front Physiol 4, 152 crossref(new window)

Kim JO, Song DW, Kwon EJ et al (2015) miR-185 plays an Anti-Hypertrophic Role in the Heart via Multiple Targets in the Calcium-Signaling Pathways. PLoS One 10, e0122509 crossref(new window)

Cook AR, Bardswell SC, Pretheshan S et al (2009) Paradoxical resistance to myocardial ischemia and age-related cardiomyopathy in NHE1 transgenic mice: a role for ER stress?. J Mol Cell Cardiol 46, 225-233 crossref(new window)

Okada K, Minamino T, Tsukamoto Y et al (2004) Prolonged endoplasmic reticulum stress in hypertrophic and failing heart after aortic constriction: possible contribution of endoplasmic reticulum stress to cardiac myocyte apoptosis. Circulation 110, 705-712 crossref(new window)

Ma Y and Hendershot LM (2004) The role of the unfolded protein response in tumour development: friend or foe?. Nat Rev Cancer 4, 966-977 crossref(new window)

Lindholm D, Wootz H and Korhonen L (2006) ER stress and neurodegenerative diseases. Cell Death Differ 13, 385-392 crossref(new window)

Chhabra R, Dubey R and Saini N (2011) Gene expression profiling indicate role of ER stress in miR-23a~27a~24-2 cluster induced apoptosis in HEK293T cells. RNA Biol 8, 648-664 crossref(new window)

Yang F, Zhang L, Wang F et al (2011) Modulation of the unfolded protein response is the core of microRNA-122-involved sensitivity to chemotherapy in hepatocellular carcinoma. Neoplasia 13, 590-600 crossref(new window)

Cingolani HE and Ennis IL (2007) Sodium-hydrogen exchanger, cardiac overload, and myocardial hypertrophy. Circulation 115, 1090-1100 crossref(new window)

Karki P and Fliegel L (2010) Overexpression of the NHE1 isoform of the Na+/H+ exchanger causes elevated apoptosis in isolated cardiomyocytes after hypoxia/reoxygenation challenge. Mol Cell Biochem 338, 47-57 crossref(new window)

S. Engelhardt (2002) Inhibition of Na+-H+ exchange prevents hypertrophy, fibrosis, and heart failure in beta1-adrenergic receptor transgenic mice. Circ Res 90, 814-819 crossref(new window)

Javadov S, Choi A, Rajapurohitam V, Zeidan A, Basnakian AG and Karmazyn M (2008) NHE-1 inhibition-induced cardioprotection against ischaemia/reperfusion is associated with attenuation of the mitochondrial permeability transition. Cardiovasc Res 77, 416-424 crossref(new window)

Teshima Y, Akao M, Jones SP and Marbán E (2003) Cariporide (HOE642), a selective Na+-H+ exchange inhibitor, inhibits the mitochondrial death pathway. Circulation 108, 2275-2281 crossref(new window)

Von Harsdorf R, Li PF and Dietz R (1999) Signaling pathways in reactive oxygen species induced cardiomyocyte apoptosis. Circulation 99, 2934-2941 crossref(new window)

Garciarena CD, Caldiz CI, Correa MV et al (2008) Na+/H+ exchanger-1 inhibitors decrease myocardial superoxide production via direct mitochondrial action. J Appl Physiol 105, 1706-1713 crossref(new window)

Maron BJ, Ferrans VJ and Roberts WC (1975) Myocardial ultrastructure in patients with chronic aortic valve disease. Am J Cardiol 35, 725-739 crossref(new window)

Park CS, Cha H, Kwon EJ, Sreenivasaiah PK and Kim DH (2012) The chemical chaperone 4-phenylbutyric acid attenuates pressure-overload cardiac hypertrophy by alleviating endoplasmic reticulum stress. Biochem Biophys Res Commun 421, 578-584 crossref(new window)

Backs J, Song K, Bezprozvannaya S, Chang S and Olson EN (2006) CaM kinase II selectively signals to histone deacetylase 4 during cardiomyocyte hypertrophy. J Clin Invest 116, 1853-1864 crossref(new window)

Eckstein LA, Van Quill KR, Bui SK, Uusitalo MS and O’Brien JM (2005) Cyclosporin A inhibits calcineurin/nuclear factor of activated T-cells signaling and induces apoptosis in retinoblastoma cells. Investig Ophthalmol Vis Sci 46, 782-790 crossref(new window)

Matsuda T, Arakawa N, Takuma K et al (2001) SEA0400, a novel and selective inhibitorof the Na+-Ca2+ exchanger, attenuates reperfusion injury in the in vitro and in vivo cerebral ischemic models. J Pharmacol Exp Ther 298, 249-256