A Soluble Epoxide Hydrolase Inhibitor Upregulated KCNJ12 and KCNIP2 by Downregulating MicroRNA-29 in a Mouse Model of Myocardial Infarction
Keywords:Soluble epoxide hydrolase inhibitors, miR-29, Ischemic arrhythmia
Background: Soluble epoxide hydrolase inhibitors (sEHi) have anti-arrhythmic effects, and we previously found that the novel sEHi t-AUCB (trans-4[-4-(3-adamantan-1-yl-ureido)-cyclohexyloxy]-benzoic acid) significantly inhibited ventricular arrhythmias after myocardial infarction (MI). However, the mechanism is unknown. It’s known that microRNA-29 (miR-29) participates in the occurrence of arrhythmias. In this study, we investigated whether sEHi t-AUCB was protective against ischemic arrhythmias by modulating miR-29 and its target genes KCNJ12 and KCNIP2.
Methods: Male 8-week-old C57BL/6 mice were divided into five groups and fed distilled water only or distilled water with t-AUCB of different dosages for seven days. Then, the mice underwent MI or sham surgery. The ischemic region of the myocardium was obtained 24 hours after MI to detect miR-29, KCNJ12, and KCNIP2 mRNA expression levels via real-time PCR and KCNJ12 and KCNIP2 protein expression levels via western blotting.
Results: MiR-29 expression levels were significantly increased in the ischemic region of MI mouse hearts and the mRNA and protein expression levels of its target genes KCNJ12 and KCNIP2 were significantly decreased. T-AUCB prevented these changes dose-dependently.
Conclusion: The sEHi t-AUCB regulates the expression levels of miR-29 and its target genes KCNJ12 and KCNIP2, suggesting a possible mechanism for its potential therapeutic application in ischemic arrhythmia.
Alexandre J, Hof T, Puddu PE, et al. 2015. Rapid and MR-Independent IK1 Activation by Aldosterone during Ischemia-Reperfusion. PloS one 10:e0132592.
Boštjančič E and Glavač D. 2014. miRNome in myocardial infarction: Future directions and perspective. World J Cardiology 6:939-58.
Červenka L, Husková Z, Kopkan L, et al. 2018. Two pharmacological epoxyeicosatrienoic acid-enhancing therapies are effectively antihypertensive and reduce the severity of ischemic arrhythmias in rats with angiotensin II-dependent hypertension. Journal of hypertension 36:1326-41.
Dawson K, Wakili R, Ordög B, et al. 2013. MicroRNA29: a mechanistic contributor and potential biomarker in atrial fibrillation. Circulation 127:10.1161.
Deschênes I, DiSilvestre D, Juang GJ, et al. 2002. Regulation of Kv4.3 current by KChIP2 splice variants: a component of native cardiac I(to)? Circulation 106:423-9.
Domenighetti AA, Boixel C, Cefai D, et al. 2007. Chronic angiotensin II stimulation in the heart produces an acquired long QT syndrome associated with IK1 potassium current downregulation. Journal of molecular and cellular cardiology 42:63-70.
Dong S, Cheng Y, Yang J, et al. 2009. MicroRNA expression signature and the role of microRNA-21 in the early phase of acute myocardial infarction. J Biol Chem 284:29514-25.
Gui Y-J, Yang T, Liu Q, et al. 2017. Soluble epoxide hydrolase inhibitors, t-AUCB, regulated microRNA-1 and its target genes in myocardial infarction mice. Oncotarget 8:94635-49.
Gui Y, Li D, Chen J, et al. 2018. Soluble epoxide hydrolase inhibitors, t-AUCB, downregulated miR-133 in a mouse model of myocardial infarction. Lipids Health Dis 17:129.
Guo Y, Luo F, Zhang X, et al. 2018. TPPU enhanced exercise-induced epoxyeicosatrienoic acid concentrations to exert cardioprotection in mice after myocardial infarction. Journal of cellular and molecular medicine 22:1489-1500.
He J, Wang C, Zhu Y, et al. 2016. Soluble epoxide hydrolase: A potential target for metabolic diseases. J Diabetes 8:305-13.
Inceoglu B, Schmelzer KR, Morisseau C, et al. 2007. Soluble epoxide hydrolase inhibition reveals novel biological functions of epoxyeicosatrienoic acids (EETs). Prostaglandins & other lipid mediators 82:42-9.
Lin Y, Sibanda VL, Zhang H-M, et al. 2015. MiRNA and TF co-regulatory network analysis for the pathology and recurrence of myocardial infarction. Scientific Rep 5:9653.
Liu L, Hayashi K, Kaneda T, et al. 2013. A novel mutation in the transmembrane nonpore region of the KCNH2 gene causes severe clinical manifestations of long QT syndrome. Heart Rhythm 10:61-7.
Liu X, Zhang Y, Du W, et al. 2016. MiR-223-3p as a novel microRNA regulator of expression of voltage-gated K+ channel Kv4.2 in acute myocardial infarction. Cellular Physiol Biochem 39:102-14.
Liu Q, Zhao X, Peng R, et al. 2017. Soluble epoxide hydrolase inhibitors might prevent ischemic arrhythmias via microRNA-1 repression in primary neonatal mouse ventricular myocytes. Molecular Bio Systems 13:556-64.
Lundby A, Jespersen T, Schmitt N, et al. 2010. Effect of the I(to) activator NS5806 on cloned K(V)4 channels depends on the accessory protein KChIP2. British J Pharmacol 160:2028-44.
Myers R, Timofeyev V, Li N, et al. 2015. Feedback mechanisms for cardiac-specific microRNAs and cAMP signaling in electrical remodeling. Circ Arrhyth and Electrophysiol 8:942-50.
Obukhov AG, Scherer D, Seyler C, et al. 2016. Inhibition of cardiac kir current (IK1) by protein kinase C critically depends on PKCβ and Kir2.2. Plos One 11.
Port JD, Walker LA, Polk J, et al. 2011. Temporal expression of miRNAs and mRNAs in a mouse model of myocardial infarction. Physiological genomics 43:1087-95.
Samokhvalov V, Vriend J, Jamieson KL, et al. 2014. PPARγ signaling is required for mediating EETs protective effects in neonatal cardiomyocytes exposed to LPS. Frontiers in pharmacology 5:242.
Shi B, Guo Y, Wang J, et al. 2010. Altered expression of microRNAs in the myocardium of rats with acute myocardial infarction. BMC cardiovascular disorders 10:11.
Sirish P, Li N, Timofeyev V, et al. 2016. Molecular mechanisms and new treatment paradigm for atrial fibrillation. Circ Arrhyth Electrophysiol 9:10.1161.
Spector AA. 2009. Arachidonic acid cytochrome P450 epoxygenase pathway. J Lipid Res 50 Suppl:S52-6.
Talman V and Ruskoaho H. 2016. Cardiac fibrosis in myocardial infarction-from repair and remodeling to regeneration. Cell and Tissue Res 365:563-81.
Thireau J, Zalvidea S, Meschin P, et al. 2015. ACE inhibitor delapril prevents Ca(2+)-dependent blunting of IK1 and ventricular arrhythmia in ischemic heart disease. Current Mol Med 15:642-51.
Ulu A, Davis BB, Tsai H-J, et al. 2008. Soluble epoxide hydrolase inhibitors reduce the development of atherosclerosis in apolipoprotein e-knockout mouse model. J Cardiovasc Pharmacol 52:314-23.
van Rooij E, Sutherland LB, Thatcher JE, et al. 2008. Dysregulation of microRNAs after myocardial infarction reveals a role of miR-29 in cardiac fibrosis. Proc Natl Acad Sci USA 105:13027-32.
Wei X, Hou X, Li J, et al. 2017. miRNA-181a/b Regulates Phenotypes of Vessel Smooth Muscle Cells Through Serum Response Factor. DNA and Cell Biol 36:127-35.
Xu D-y, Davis BB, Wang Z-h, et al. 2013. A potent soluble epoxide hydrolase inhibitor, t-AUCB, acts through PPARγ to modulate the function of endothelial progenitor cells from patients with acute myocardial infarction. Int J Cardiol 167:1298-1304.
Yasuda S, Kobayashi H, Iwasa M, et al. 2009. .Antidiabetic drug pioglitazone protects the heart via activation of PPAR-gamma receptors, PI3-kinase, Akt, and eNOS pathway in a rabbit model of myocardial infarction. Am J Physiol Heart and Circ Physiol 296:H1558-65.
Ye Y, Hu Z, Lin Y, et al. 2010. Downregulation of microRNA-29 by antisense inhibitors and a PPAR-gamma agonist protects against myocardial ischaemia-reperfusion injury. Cardiovasc Res 87:535-44.
Yeboah MM, Hye Khan MA, Chesnik MA, et al. 2016. The epoxyeicosatrienoic acid analog PVPA ameliorates cyclosporine-induced hypertension and renal injury in rats. Am J Physiol Renal Physiol 311:F576-85.
Zaritsky JJ, Redell JB, Tempel BL, et al. 2001. The consequences of disrupting cardiac inwardly rectifying K(+) current (I(K1)) as revealed by the targeted deletion of the murine Kir2.1 and Kir2.2 genes. J Physiol (Lond) 2533:697-710.
Zhai X-W, Zhang L, Guo Y-F, et al. 2017. The IK1/Kir2.1 channel agonist zacopride prevents and cures acute ischemic arrhythmias in the rat. PloS one 12:e0177600.
Zhang X, Azhar G, Helms SA, et al. 2011. Regulation of cardiac microRNAs by serum response factor. Journal of biomedical science 18:15.
Zhao Y, Yuan Y and Qiu C. 2016. Underexpression of CACNA1C caused by overexpression of microRNA-29a underlies the pathogenesis of atrial fibrillation. Med Sci Monitor 22:2175-81.
Zhou S-S, Jin J-P, Wang J-Q, et al. 2018. miRNAS in cardiovascular diseases: potential biomarkers, therapeutic targets and challenges. Acta pharmacologica Sinica 39:1073-84.
Zhu J-N, Chen R, Fu Y-H, et al. 2013. Smad3 inactivation and MiR-29b upregulation mediate the effect of carvedilol on attenuating the acute myocardium infarction-induced myocardial fibrosis in rat. PloS one 8:e75557.
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