title: Epigenetic silencing of TIMP4 in heart failure.
abstract: Tissue inhibitor of matrix metalloprotease 4 (TIMP4) is endogenously one of the key modulators of matrix metalloprotease 9 (MMP9) and we have reported earlier that cardiac specific TIMP4 instigates contractility and helps in differentiation of cardiac progenitor cells. Although studies show that the expression of TIMP4 goes down in heart failure but the mechanism is unknown. This study aims to determine the mechanism of silencing of TIMP4 in heart failure progression created by aorta-vena cava (AV) fistula. We hypothesize that there is epigenetic silencing of TIMP4 in heart failure. To validate this hypothesis, we created heart failure model by creating AV fistula in C57BL/6 mice and looked into the promoter methylation (methylation specific PCR, high resolution melting, methylation sensitive restriction enzyme and Na bisulphite treatment followed by sequencing), histone modification (ChIP assay) and microRNAs that regulate TIMP4 (mir122a) and MMP9 (mir29b and mir455-5p). The physiological parameters in terms of cardiac function after AV fistula were assessed by echocardiography. We observed that there are 7 CpG islands in the TIMP4 promoter which get methylated during the progression of heart failure which leads to its epigenetic silencing. In addition, the up-regulated levels of mir122a in part, contribute to regulation of TIMP4. Consequently, MMP9 gets up-regulated and leads to cardiac remodeling. This is a novel report to explain the epigenetic silencing of TIMP4 in heart failure.
authors.affiliation: Department of Physiology and Biophysics, School of Medicine, University of Louisville, Louisville, KY, USA. p0chat03@louisville.edu.
authors.forename: Pankaj
authors.initials: P
authors.lastname: Chaturvedi
authors.affiliation: Department of Physiology and Biophysics, School of Medicine, University of Louisville, Louisville, KY, USA.
authors.forename: Suresh C
authors.initials: SC
authors.lastname: Tyagi
mesh_terms: D000107:Acetylation; D000818:Animals; D001164:Arteriovenous Fistula / Q000150:complications; D001483:Base Sequence; D018899:CpG Islands / Q000235:genetics; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000378:metabolism; D019175:DNA Methylation / Q000235:genetics; D015536:Down-Regulation / Q000235:genetics; D044127:Epigenesis, Genetic; D020868:Gene Silencing; D006333:Heart Failure / Q000209:etiology / Q000235:genetics* / Q000503:physiopathology; D006334:Heart Function Tests; D056284:Histone Deacetylase 1 / Q000378:metabolism; D007150:Immunohistochemistry; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism; D008954:Models, Biological; D009691:Nucleic Acid Denaturation; D011401:Promoter Regions, Genetic; D015183:Restriction Mapping; D019714:Tissue Inhibitor of Metalloproteinases / Q000235:genetics* / Q000378:metabolism; D015854:Up-Regulation / Q000235:genetics; D000097792:Tissue Inhibitor of Metalloproteinase-4
chemical_list: D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases; D056284:Histone Deacetylase 1; D020780:Matrix Metalloproteinase 9; D035683:MicroRNAs; D019714:Tissue Inhibitor of Metalloproteinases; D000097792:Tissue Inhibitor of Metalloproteinase-4; C484389:Hdac1 protein, mouse
keywords: epigenetic silencing; heart failure; tissue inhibitor of matrix metalloprotease