MicroRNA Expression Signature and the Role of MicroRNA-21 in the Early Phase of Acute Myocardial Infarction

Abstract

Several recent reports have suggested that microRNAs (miRNAs) might play critical roles in acute myocardial infarction (AMI). However, the miRNA expression signature in the early phase of AMI has not been identified. In this study, the miRNA expression signature was investigated in rat hearts 6 h after AMI. Compared with the expression signature in the noninfarcted areas, 38 miRNAs were differentially expressed in infarcted areas and 33 miRNAs were aberrantly expressed in the border areas. Remarkably, miR-21 expression was significantly down-regulated in infarcted areas, but was up-regulated in border areas. The down-regulation of miR-21 in the infarcted areas was inhibited by ischemic preconditioning, a known cardiac protective method. Overexpression of miR-21 via adenovirus expressing miR-21 (Ad-miR-21) decreased myocardial infarct size by 29% at 24 h and decreased the dimension of left ventricles at 2 weeks after AMI. Using both gain-of-function and loss-of-function approaches in cultured cardiac myocytes, we identified that miR-21 had a protective effect on ischemia-induced cell apoptosis that was associated with its target gene programmed cell death 4 and activator protein 1 pathway. The protective effect of miR-21 against ischemia-induced cardiac myocyte damage was further confirmed in vivo by decreased cell apoptosis in the border and infarcted areas of the infarcted rat hearts after treatment with Ad-miR-21. The results suggest that miRNAs such as miR-21 may play critical roles in the early phase of AMI. Several recent reports have suggested that microRNAs (miRNAs) might play critical roles in acute myocardial infarction (AMI). However, the miRNA expression signature in the early phase of AMI has not been identified. In this study, the miRNA expression signature was investigated in rat hearts 6 h after AMI. Compared with the expression signature in the noninfarcted areas, 38 miRNAs were differentially expressed in infarcted areas and 33 miRNAs were aberrantly expressed in the border areas. Remarkably, miR-21 expression was significantly down-regulated in infarcted areas, but was up-regulated in border areas. The down-regulation of miR-21 in the infarcted areas was inhibited by ischemic preconditioning, a known cardiac protective method. Overexpression of miR-21 via adenovirus expressing miR-21 (Ad-miR-21) decreased myocardial infarct size by 29% at 24 h and decreased the dimension of left ventricles at 2 weeks after AMI. Using both gain-of-function and loss-of-function approaches in cultured cardiac myocytes, we identified that miR-21 had a protective effect on ischemia-induced cell apoptosis that was associated with its target gene programmed cell death 4 and activator protein 1 pathway. The protective effect of miR-21 against ischemia-induced cardiac myocyte damage was further confirmed in vivo by decreased cell apoptosis in the border and infarcted areas of the infarcted rat hearts after treatment with Ad-miR-21. The results suggest that miRNAs such as miR-21 may play critical roles in the early phase of AMI. MicroRNAs (miRNAs) 3The abbreviations used are: miRNAmicroRNATTCtriphenyltetrazolium chloridem.o.i.multiplicity of infectionqRTquantitative reverse transcriptasepfuplaque-forming unitTUNELterminal deoxynucleotide transferase dUTP nick end labelingAMIacute myocardial infarctionIPischemic preconditioningPDCD4programmed cell death 4AdadenovirusGFPgreen fluorescent proteinLVleft ventricleH/Rhypoxia/reoxygenationLNAlacked nucleic acid. 3The abbreviations used are: miRNAmicroRNATTCtriphenyltetrazolium chloridem.o.i.multiplicity of infectionqRTquantitative reverse transcriptasepfuplaque-forming unitTUNELterminal deoxynucleotide transferase dUTP nick end labelingAMIacute myocardial infarctionIPischemic preconditioningPDCD4programmed cell death 4AdadenovirusGFPgreen fluorescent proteinLVleft ventricleH/Rhypoxia/reoxygenationLNAlacked nucleic acid. are endogenous, noncoding, single-stranded RNAs of ∼22 nucleotides and constitute a novel class of gene regulators (1Ambros V. Cell. 2003; 113: 673-676Abstract Full Text Full Text PDF PubMed Scopus (1090) Google Scholar, 2Farh K.K. Grimson A. Jan C. Lewis B.P. Johnston W.K. Lim L.P. Burge C.B. Bartel D.P. Science. 2005; 310: 1817-1821Crossref PubMed Scopus (1264) Google Scholar, 3Pasquinelli A.E. Hunter S. Bracht J. Curr. Opin. Genet. Dev. 2005; 15: 200-205Crossref PubMed Scopus (259) Google Scholar). Analogous to the first RNA revolution in the 1980s, when Zaug and Cech (4Zaug A.J. Cech T.R. Science. 1986; 231: 470-475Crossref PubMed Scopus (395) Google Scholar) discovered the enzymatic activity of RNA, the more recent discoveries of RNA interference and miRNA may represent the second RNA revolution (5Kong Y. Han J.H. Genomics Proteomics Bioinformatics. 2005; 3: 62-72Crossref PubMed Scopus (40) Google Scholar). Although the first miRNA, lin-4, was discovered in 1993 (6Lee R.C. Feinbaum R.L. Ambros V. Cell. 1993; 75: 843-854Abstract Full Text PDF PubMed Scopus (9648) Google Scholar, 7Wightman B. Ha I. Ruvkun G. Cell. 1993; 75: 855-862Abstract Full Text PDF PubMed Scopus (3117) Google Scholar), their presence in vertebrates was confirmed only in 2001 (8Lagos-Quintana M. Rauhut R. Lendeckel W. Tuschl T. Science. 2001; 294: 853-858Crossref PubMed Scopus (3935) Google Scholar). miRNAs are initially transcribed in the nucleus by RNA polymerase II or III to form large pri-miRNA transcripts (9Kim V.N. Nat. Rev. Mol. Cell Biol. 2005; 6: 376-385Crossref PubMed Scopus (1992) Google Scholar). These pri-miRNAs are then processed by the RNase III enzymes, Drosha, Pasha, and Dicer, to generate 18- to 24-nucleotide mature miRNAs. In addition to this miRNA biogenesis pathway, some miRNA precursors are able to bypass Drosha processing to produce miRNAs via Dicer, possibly representing an alternative pathway for miRNA biogenesis (10Kim Y.K. Kim V.N. EMBO J. 2007; 26: 775-783Crossref PubMed Scopus (607) Google Scholar, 11Ruby J.G. Jan C.H. Bartel D.P. Nature. 2007; 448: 83-86Crossref PubMed Scopus (1132) Google Scholar). The mature miRNAs bind to the 3′-untranslated region of their mRNA targets and negatively regulate gene expression via degradation or translational inhibition. microRNA triphenyltetrazolium chloride multiplicity of infection quantitative reverse transcriptase plaque-forming unit terminal deoxynucleotide transferase dUTP nick end labeling acute myocardial infarction ischemic preconditioning programmed cell death 4 adenovirus green fluorescent protein left ventricle hypoxia/reoxygenation lacked nucleic acid. microRNA triphenyltetrazolium chloride multiplicity of infection quantitative reverse transcriptase plaque-forming unit terminal deoxynucleotide transferase dUTP nick end labeling acute myocardial infarction ischemic preconditioning programmed cell death 4 adenovirus green fluorescent protein left ventricle hypoxia/reoxygenation lacked nucleic acid. Currently, about 600 miRNAs have been cloned and sequenced in humans, and the estimated number of miRNA genes is as high as 1,000 in the human genome (12Bentwich I. Avniel A. Karov Y. Aharonov R. Gilad S. Barad O. Barzilai A. Einat P. Einav U. Meiri E. Sharon E. Spector Y. Bentwich Z. Nat. Genet. 2005; 37: 766-770Crossref PubMed Scopus (1561) Google Scholar, 13Berezikov E. Guryev V. van de Belt J. Wienholds E. Plasterk R.H. Cuppen E. Cell. 2005; 120: 21-24Abstract Full Text Full Text PDF PubMed Scopus (1063) Google Scholar). Functionally, an individual miRNA is as important as a transcription factor because it is able to regulate the expression of its multiple target genes. As a group, miRNAs are estimated to regulate over 30% of the genes in a cell (14Lewis B.P. Burge C.B. Bartel D.P. Cell. 2005; 120: 15-20Abstract Full Text Full Text PDF PubMed Scopus (9835) Google Scholar). It is thus not surprising that miRNAs are involved in the regulation of almost all major cellular functions including apoptosis and necrosis, which are two key cellular events in acute myocardial infarction (AMI). AMI has long been the leading cause of death in developed countries. Several recent reports have suggested that miRNAs might play critical roles in the pathophysiology of AMI (15Yang B. Lin H. Xiao J. Lu Y. Luo X. Li B. Zhang Y. Xu C. Bai Y. Wang H. Chen G. Wang Z. Nat. Med. 2007; 13: 486-491Crossref PubMed Scopus (960) Google Scholar, 16Ikeda S. Kong S.W. Lu J. Bisping E. Zhang H. Allen P.D. Golub T.R. Pieske B. Pu W.T. Physiol. Genomics. 2007; 31: 367-373Crossref PubMed Scopus (537) Google Scholar, 17Wang S. Aurora A.B. Johnson B.A. Qi X. McAnally J. Hill J.A. Richardson J.A. Bassel-Duby R. Olson E.N. Dev. Cell. 2008; 15: 261-271Abstract Full Text Full Text PDF PubMed Scopus (1471) Google Scholar, 18van Rooij E. Sutherland L.B. Thatcher J.E. DiMaio J.M. Naseem R.H. Marshall W.S. Hill J.A. Olson E.N. Proc. Natl. Acad. Sci. U.S.A. 2008; 105: 13027-13032Crossref PubMed Scopus (1492) Google Scholar, 19Yin C. Wang X. Kukreja R.C. FEBS Lett. 2008; 582: 4137-4142Crossref PubMed Scopus (103) Google Scholar). Yang et al. (15Yang B. Lin H. Xiao J. Lu Y. Luo X. Li B. Zhang Y. Xu C. Bai Y. Wang H. Chen G. Wang Z. Nat. Med. 2007; 13: 486-491Crossref PubMed Scopus (960) Google Scholar) have found that the expression of a cardiac arrhythmia-related miRNA, miR-1, is increased in human hearts with coronary heart disease and in rat hearts with AMI. The results of miR-1 expression change in human hearts with coronary artery disease are still controversial, because another recent study has demonstrated that the miR-1 expression tends to be down-regulated in human hearts with coronary artery disease (16Ikeda S. Kong S.W. Lu J. Bisping E. Zhang H. Allen P.D. Golub T.R. Pieske B. Pu W.T. Physiol. Genomics. 2007; 31: 367-373Crossref PubMed Scopus (537) Google Scholar). The potential involvement of miRNAs in AMI is also suggested in a study using miR-126 null mice, in which Wang et al. (17Wang S. Aurora A.B. Johnson B.A. Qi X. McAnally J. Hill J.A. Richardson J.A. Bassel-Duby R. Olson E.N. Dev. Cell. 2008; 15: 261-271Abstract Full Text Full Text PDF PubMed Scopus (1471) Google Scholar) have found that the survival rate in miR-126-deficient mice following AMI is significantly reduced compared with that in wild-type mice. The expression signature in the late phase of AMI (3 and 14 days after AMI) has just been identified by an excellent study reported by van Rooij et al. (18van Rooij E. Sutherland L.B. Thatcher J.E. DiMaio J.M. Naseem R.H. Marshall W.S. Hill J.A. Olson E.N. Proc. Natl. Acad. Sci. U.S.A. 2008; 105: 13027-13032Crossref PubMed Scopus (1492) Google Scholar). These investigators found that miR-29 plays an important role in cardiac fibrosis during the repair process after AMI. During manuscript another excellent study was reported by C. Wang X. Kukreja R.C. FEBS Lett. 2008; 582: 4137-4142Crossref PubMed Scopus (103) Google Scholar). In an in have found in hearts with miRNAs including myocardial infarct size after in is the miRNA expression signature in the early phase of AMI has not been identified. the potential of miRNA treatment on myocardial infarct size in an in vivo AMI have not been The of the study was to the expression of areas in infarcted rat hearts at 6 h after AMI and to the role of an aberrantly expressed miRNA, in AMI and its potential cellular and the miRNA expression in infarcted we a rat AMI using left coronary artery as T. A. A. M. B. H. J. Physiol. Physiol. PubMed Scopus Google Scholar). In were with and an AMI was by of the left coronary artery with a as involved an the was the left coronary artery was via of coronary of the left coronary artery as H. S. B. Li G. R. J. Physiol. Physiol. PubMed Scopus Google Scholar). were by the and at the of and of and were with the for the and of of 6 and 24 h after the of the coronary the were and 6 of was the to the noninfarcted of the The myocardial ischemic at was identified as the region The ventricles of the hearts were The were in triphenyltetrazolium chloride at for to the noninfarcted and infarcted areas. size was expressed as a of the ischemic at In myocardial noninfarcted was as the The infarcted was as the The border was identified as and areas. weeks after the rat hearts were in by an of chloride via the left The of the were in at the of as S. P. T. O. J. V. J. PubMed Scopus (40) Google Scholar, B. Wang X. Li PubMed Scopus Google Scholar). miRNAs were the and noninfarcted areas of rat left ventricles at 6 h after left coronary artery using the miRNA miRNAs the were used as the In of miRNAs were rat left ventricles at 6 h after had and miRNA expression was by miRNA using a mature miRNAs Y. X. Zhang S. Lin Y. Yang J. Zhang C. J. Mol. Cell. Full Text Full Text PDF PubMed Scopus Google Scholar, R. Y. J. Yang J. X. Chen H. Zhang C. 2007; PubMed Scopus Google Scholar). The miRNA expression was demonstrated by the of the 6 were used at of the The adenovirus expressing miR-21 or adenovirus expressing were using the 2 to the These were by chloride and using a or were the rat hearts days AMI as U. T. A. Proc. Natl. Acad. Sci. U.S.A. PubMed Scopus Google Scholar). were with and The was via the The and artery were identified. of adenovirus was the of the left ventricle to the The and were to the of the and the was The was for when the heart against a the that the adenovirus to the coronary and the on the and artery were and the was of rat cardiac were as (12Bentwich I. Avniel A. Karov Y. Aharonov R. Gilad S. Barad O. Barzilai A. Einat P. Einav U. Meiri E. Sharon E. Spector Y. Bentwich Z. Nat. Genet. 2005; 37: 766-770Crossref PubMed Scopus (1561) Google Scholar). In hearts were in the were and the ventricles were with The and were by with and I. were cultured in cardiac myocyte with 4 of of 2 of of of of of of and and Cell ischemic by in a and and was as J.H. T. Yang Y. Lim J. 2007; PubMed Scopus (40) Google Scholar). was by the in a with and at for 4 the were with and for h in and was to an Y. X. Zhang S. Lin Y. Yang J. Zhang C. J. Mol. Cell. Full Text Full Text PDF PubMed Scopus Google Scholar, R. Y. J. Yang J. X. Chen H. Zhang C. 2007; PubMed Scopus Google Scholar). the miR-21 miR-21 was to the at a of miR-21 was to the at a of gene was by The was 4 h by for and and adenovirus were aberrantly expressed miRNAs in infarcted hearts were further confirmed by Y. X. Zhang S. Lin Y. Yang J. Zhang C. J. Mol. Cell. Full Text Full Text PDF PubMed Scopus Google Scholar, R. Y. J. Yang J. X. Chen H. Zhang C. 2007; PubMed Scopus Google Scholar). as miR-21 is the miRNA for the study, its expression in hearts and in areas of the infarcted hearts was at 6 and 24 h after AMI. In was also used to the miR-21 in cultured was on of RNA using the of the miRNA and of were with a As an was used for The used were by were to an and the was the phase of the The gene expression was by for target The target were by the which the The expression was then using the following gene expression cultured cardiac were by of protein were to was using Cell was used as the protein 1 activity was using as H. Kim Yang 2007; PubMed Scopus Google Scholar). by a with of the transcription for was cardiac with or for 4 h were with for h with activity was after 24 h using a and to protein cardiac myocyte apoptosis and apoptosis in heart were by terminal deoxynucleotide transferase dUTP nick end labeling as Y. X. Zhang S. Lin Y. Yang J. Zhang C. J. Mol. Cell. Full Text Full Text PDF PubMed Scopus Google Scholar, R. Y. J. Yang J. X. Chen H. Zhang C. 2007; PubMed Scopus Google Scholar). cardiac cultured on in were in In heart was in heart The was using the in cell death to the The of and the in infarcted and border areas were a The and noninfarcted areas were identified by in and heart are as gene the of the was as or and of were used for of the The was used for was Compared with in the noninfarcted areas, miRNAs were aberrantly expressed in both infarcted and border areas of the infarcted hearts at 6 h after AMI. the 38 miRNAs were differentially expressed and in the infarcted areas with over 30% change and In the border areas, 33 miRNAs were differentially expressed and 14 Although of the miRNAs had a expression in the noninfarcted of the infarcted hearts compared with the the expression of some miRNAs in the two was still and were but and were down-regulated in the noninfarcted areas of the infarcted expression of miRNAs in the infarcted of rat hearts at 6 h after in noninfarcted in infarcted in a expression of miRNAs in border of the rat hearts at 6 h after in noninfarcted in border in a aberrantly expressed miRNAs in infarcted areas were further by Remarkably, miR-21 expression in the infarcted areas was significantly decreased compared with that in noninfarcted further the expression of miR-21 in the areas of the infarcted hearts and its in the early phase of miRNAs were in the areas of the infarcted hearts as as in hearts at 6 and 24 h after AMI. As in miR-21 expression was down-regulated in the infarcted areas at both 6 and 24 h after AMI compared with that in areas and in compared with that in areas and in miR-21 expression in border areas was significantly In miR-21 expression in noninfarcted areas of the infarcted hearts was also that in is a to the heart against myocardial further the involvement of miR-21 in the effect of on miR-21 was As in 6 h after the expression in rat hearts was In infarcted rat the down-regulated expression of miR-21 in infarcted areas was In border and noninfarcted areas, in an in miR-21 expression in hearts at 6 h after AMI The of on the expression of miRNAs that were aberrantly expressed in the infarcted of the rat hearts by are in 3The of on the expression of miRNAs that are aberrantly expressed in the infarcted of the rat in in in a As in at days after increased miR-21 expression in rat hearts in a on the of we the using at days AMI. As in compared with adenovirus reduced myocardial infarct size by at 24 h after AMI. heart with or are in the potential cellular protective during myocardial an cell was in which to the cultured was by in a and by in found that the miR-21 but increased miR-21 expression in cultured cardiac As hypoxia/reoxygenation in an in decreased cardiac myocyte apoptosis In cardiac myocyte apoptosis was after treatment with cardiac and cardiac with or are in The results that miR-21 has a protective effect against ischemia-induced cardiac myocyte apoptosis in that the cell protective effect is miR-21 we also the effect of which has expression in the heart and has expression during the AMI on cell As in had effect on cardiac myocyte the cellular involved in the protective effect against myocardial infarction in apoptosis was in infarcted heart by with The areas were further identified by in and as in and the were identified by with in heart with or are in The at 24 h after were in both infarcted and border areas. As in compared with the group, apoptosis of the cardiac in both the border and infarcted areas was significantly decreased in the The results that the protective effect against myocardial infarction is to its effect on cardiac in The reduced myocardial size and heart cell apoptosis have results on such as change in the infarcted hearts both and were at 2 weeks after AMI. As in the in was significantly that in that is a potential target gene of miR-21 as in recent study Y. X. Zhang S. Lin Y. Yang J. Zhang C. J. Mol. Cell. Full Text Full Text PDF PubMed Scopus Google Scholar). The role of in cardiac cell apoptosis is this we by in cultured cardiac As in expression was increased by in cardiac with the increased cardiac myocyte apoptosis by hypoxia/reoxygenation In expression in cardiac was up-regulated by but down-regulated by The results suggest that is a miR-21 target gene that is involved in on cardiac might be a of that is associated with the effect on cell apoptosis J.H. T. Yang Y. Lim J. 2007; PubMed Scopus (40) Google Scholar). the potential involvement of in on cardiac activity was in cultured cardiac As in of by inhibited In expression via in a in activity In expression via in an in activity These results suggest that may be a of that is to the effect on cardiac It is that AMI is a process in which multiple genes have been found to be R. Med. 2007; Full Text Full Text PDF PubMed Scopus Google Scholar). miRNAs are a novel of gene regulators that regulate over 30% of genes in a It is to that miRNAs be involved in AMI. The study demonstrated for the first that multiple miRNAs were aberrantly expressed in the early phase of AMI both in the border and infarcted areas. The multiple miRNAs found in this study the of AMI. after of the coronary artery early myocyte by and infarction the of its (8Lagos-Quintana M. Rauhut R. Lendeckel W. Tuschl T. Science. 2001; 294: 853-858Crossref PubMed Scopus (3935) Google Scholar). after are still some ischemic and the infarction The border an excellent for AMI. important in the study is that the miRNA signature in the border is that of the infarcted of the infarcted that some of the aberrantly expressed miRNAs might have AMI in the study is that the expression of some miRNAs in the at 6 h after AMI is also that in is with a recent by van Rooij et al. (18van Rooij E. Sutherland L.B. Thatcher J.E. DiMaio J.M. Naseem R.H. Marshall W.S. Hill J.A. Olson E.N. Proc. Natl. Acad. Sci. U.S.A. 2008; 105: 13027-13032Crossref PubMed Scopus (1492) Google Scholar), in which investigators also found that the expression of some miRNAs in the of hearts in the late phase of AMI (3 and 14 days after AMI) is that in These results suggest that some miRNAs in the might also in the to AMI. recent has that miR-1 is up-regulated in ischemic heart (15Yang B. Lin H. Xiao J. Lu Y. Luo X. Li B. Zhang Y. Xu C. Bai Y. Wang H. Chen G. Wang Z. Nat. Med. 2007; 13: 486-491Crossref PubMed Scopus (960) Google Scholar). However, another recent study has demonstrated that miR-1 expression tends to be down-regulated in human hearts with coronary heart disease (16Ikeda S. Kong S.W. Lu J. Bisping E. Zhang H. Allen P.D. Golub T.R. Pieske B. Pu W.T. Physiol. Genomics. 2007; 31: 367-373Crossref PubMed Scopus (537) Google Scholar). In the study, we found that miR-1 is significantly down-regulated in the infarcted areas at 6 h after AMI. The for the in miR-1 expression are However, the in disease and for might be for the we have found that the expression of multiple miRNAs is in the areas of the infarcted hearts at 6 h after AMI. In the used in the miRNA might also the results of miRNA RNA is used as the in the miRNA is used as the in However, some the rate of degradation of RNA is not with that of that after the degradation of is that of Y. J. J. X. X. T. J. E. S. and C. of a is still an in miRNA In the study, is that miR-21 is significantly increased in the border of the infarcted hearts at both 6 and 24 h after AMI. In its expression is down-regulated in the infarcted a cardiac protective is able to reverse down-regulation of miR-21 in the infarcted further the of on cardiac miRNA a miRNA was in rat hearts at 6 h after compared with expression in the infarcted areas, an change in the expression of and In a change in the expression of and compared with that in the infarcted areas 1 and The results that aberrantly expressed miRNAs in infarcted hearts may have or on cardiac ischemic recent Y. X. Zhang S. Lin Y. Yang J. Zhang C. J. Mol. Cell. Full Text Full Text PDF PubMed Scopus Google Scholar, R. Y. J. Yang J. X. Chen H. Zhang C. 2007; PubMed Scopus Google Scholar) have that miR-21 has a effect on and in cultured heart the potential role of miR-21 in miR-21 gene was found that of miR-21 significantly the myocardial infarct size in the rat Although the of the in myocardial infarct size is the of miRNA that such a in myocardial infarct size that miRNAs may play an important role in the pathophysiology of AMI. further the cellular in on an cardiac cell was Using both gain-of-function and loss-of-function we have identified that miR-21 has an effect on cardiac in the effect of miR-21 on cardiac has been confirmed in vivo in the infarcted heart with Ad-miR-21. The reduced myocardial size and cell apoptosis following treatment in the of the hearts as by the protective effect on dimension be in to the of is a of the During manuscript we were to another their about the role of miR-21 on myocardial infarction in an in C. Wang X. Kukreja R.C. FEBS Lett. 2008; 582: 4137-4142Crossref PubMed Scopus (103) Google Scholar). study used an in vivo AMI that is their In we have identified the early expression signature of miRNAs in the of the infarcted we have demonstrated that a novel pathway, may be involved in cardiac study has further in this the of a protective effect of miR-21 on cardiac two that miR-21 is a critical miRNA to cardiac miRNAs functions via their multiple target gene Although their potential gene targets be by targets be in because on gene expression and cellular functions are cell that may be a miR-21 In the study, we have that is a target gene in cardiac we have for the first that has a effect on cardiac It is that is a key that or death cell in to E. M. 2001; PubMed Scopus Google Scholar). In the study, we have identified that is associated with which may be involved in on cardiac In miRNA in the early phase of AMI have that multiple miRNAs are aberrantly miR-21 has a protective effect on myocardial infarction by cardiac cell apoptosis via its target gene The results suggest that miRNAs may play important roles in the pathophysiology of AMI. miRNAs may be targets or for ischemic heart disease such as AMI. in for