title: Selective Blockade of Periostin Exon 17 Preserves Cardiac Performance in Acute Myocardial Infarction.
abstract: We previously reported that overexpression of full-length periostin, Pn-1, resulted in ventricular dilation with enhanced interstitial collagen deposition in a rat model. However, other reports have documented that the short-form splice variants Pn-2 (lacking exon 17) and Pn-4 (lacking exons 17 and 21) promoted cardiac repair by angiogenesis and prevented cardiac rupture after acute myocardial infarction. The apparently differing findings from those reports prompted us to use a neutralizing antibody to selectively inhibit Pn-1 by blockade of exon 17 in a rat acute myocardial infarction model. Administration of Pn neutralizing antibody resulted in a significant decrease in the infarcted and fibrotic areas of the myocardium, which prevented ventricular wall thinning and dilatation. The inhibition of fibrosis by Pn neutralizing antibody was associated with a significant decrease in gene expression of fibrotic markers, including collagen I, collagen III, and transforming growth factor-β1. Importantly, the number of α-smooth muscle actin-positive myofibroblasts was significantly reduced in the hearts of animals treated with Pn neutralizing antibody, whereas cardiomyocyte proliferation and angiogenesis were comparable in the IgG and neutralizing antibody groups. Moreover, the level of Pn-1 expression was significantly correlated with the severity of myocardial infarction. In addition, Pn-1, but not Pn-2 or Pn-4, inhibited fibroblast and myocyte attachment, which might account for the cell slippage observed during cardiac remodeling. Collectively, these results indicate that therapeutics that specifically inhibit Pn exon-17, via a neutralizing antibody or drug, without suppressing other periostin variants might offer a new class of medication for the treatment of acute myocardial infarction patients.
authors.affiliation: From the Department of Clinical Gene Therapy (Y.T., N.K., F.S., J.A., K.I., N.K., K.O., Y.I.-I., J.M., R.O., R.M.) and Department of Geriatric Medicine and Nephrology (Y.T., J.A., K.I., H.R.), Osaka University, Graduate School of Medicine, Osaka, Japan. morishit@cgt.med.osaka-u.ac.jp taniyama@cgt.med.osaka-u.ac.jp.
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Taniyama
authors.affiliation: From the Department of Clinical Gene Therapy (Y.T., N.K., F.S., J.A., K.I., N.K., K.O., Y.I.-I., J.M., R.O., R.M.) and Department of Geriatric Medicine and Nephrology (Y.T., J.A., K.I., H.R.), Osaka University, Graduate School of Medicine, Osaka, Japan.
authors.forename: Naruto
authors.initials: N
authors.lastname: Katsuragi
authors.affiliation: From the Department of Clinical Gene Therapy (Y.T., N.K., F.S., J.A., K.I., N.K., K.O., Y.I.-I., J.M., R.O., R.M.) and Department of Geriatric Medicine and Nephrology (Y.T., J.A., K.I., H.R.), Osaka University, Graduate School of Medicine, Osaka, Japan.
authors.forename: Fumihiro
authors.initials: F
authors.lastname: Sanada
authors.affiliation: From the Department of Clinical Gene Therapy (Y.T., N.K., F.S., J.A., K.I., N.K., K.O., Y.I.-I., J.M., R.O., R.M.) and Department of Geriatric Medicine and Nephrology (Y.T., J.A., K.I., H.R.), Osaka University, Graduate School of Medicine, Osaka, Japan.
authors.forename: Junya
authors.initials: J
authors.lastname: Azuma
authors.affiliation: From the Department of Clinical Gene Therapy (Y.T., N.K., F.S., J.A., K.I., N.K., K.O., Y.I.-I., J.M., R.O., R.M.) and Department of Geriatric Medicine and Nephrology (Y.T., J.A., K.I., H.R.), Osaka University, Graduate School of Medicine, Osaka, Japan.
authors.forename: Kazuma
authors.initials: K
authors.lastname: Iekushi
authors.affiliation: From the Department of Clinical Gene Therapy (Y.T., N.K., F.S., J.A., K.I., N.K., K.O., Y.I.-I., J.M., R.O., R.M.) and Department of Geriatric Medicine and Nephrology (Y.T., J.A., K.I., H.R.), Osaka University, Graduate School of Medicine, Osaka, Japan.
authors.forename: Nobutaka
authors.initials: N
authors.lastname: Koibuchi
authors.affiliation: From the Department of Clinical Gene Therapy (Y.T., N.K., F.S., J.A., K.I., N.K., K.O., Y.I.-I., J.M., R.O., R.M.) and Department of Geriatric Medicine and Nephrology (Y.T., J.A., K.I., H.R.), Osaka University, Graduate School of Medicine, Osaka, Japan.
authors.forename: Keita
authors.initials: K
authors.lastname: Okayama
authors.affiliation: From the Department of Clinical Gene Therapy (Y.T., N.K., F.S., J.A., K.I., N.K., K.O., Y.I.-I., J.M., R.O., R.M.) and Department of Geriatric Medicine and Nephrology (Y.T., J.A., K.I., H.R.), Osaka University, Graduate School of Medicine, Osaka, Japan.
authors.forename: Yuka
authors.initials: Y
authors.lastname: Ikeda-Iwabu
authors.affiliation: From the Department of Clinical Gene Therapy (Y.T., N.K., F.S., J.A., K.I., N.K., K.O., Y.I.-I., J.M., R.O., R.M.) and Department of Geriatric Medicine and Nephrology (Y.T., J.A., K.I., H.R.), Osaka University, Graduate School of Medicine, Osaka, Japan.
authors.forename: Jun
authors.initials: J
authors.lastname: Muratsu
authors.affiliation: From the Department of Clinical Gene Therapy (Y.T., N.K., F.S., J.A., K.I., N.K., K.O., Y.I.-I., J.M., R.O., R.M.) and Department of Geriatric Medicine and Nephrology (Y.T., J.A., K.I., H.R.), Osaka University, Graduate School of Medicine, Osaka, Japan.
authors.forename: Rei
authors.initials: R
authors.lastname: Otsu
authors.affiliation: From the Department of Clinical Gene Therapy (Y.T., N.K., F.S., J.A., K.I., N.K., K.O., Y.I.-I., J.M., R.O., R.M.) and Department of Geriatric Medicine and Nephrology (Y.T., J.A., K.I., H.R.), Osaka University, Graduate School of Medicine, Osaka, Japan.
authors.forename: Hiromi
authors.initials: H
authors.lastname: Rakugi
authors.affiliation: From the Department of Clinical Gene Therapy (Y.T., N.K., F.S., J.A., K.I., N.K., K.O., Y.I.-I., J.M., R.O., R.M.) and Department of Geriatric Medicine and Nephrology (Y.T., J.A., K.I., H.R.), Osaka University, Graduate School of Medicine, Osaka, Japan. morishit@cgt.med.osaka-u.ac.jp taniyama@cgt.med.osaka-u.ac.jp.
authors.forename: Ryuichi
authors.initials: R
authors.lastname: Morishita
mesh_terms: D000818:Animals; D057134:Antibodies, Neutralizing / Q000494:pharmacology*; D015815:Cell Adhesion Molecules / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics; D004195:Disease Models, Animal; D005091:Exons; D005786:Gene Expression Regulation / Q000187:drug effects; D006352:Heart Ventricles / Q000503:physiopathology*; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects*; D009203:Myocardial Infarction / Q000188:drug therapy* / Q000235:genetics / Q000503:physiopathology; D009206:Myocardium / Q000378:metabolism / Q000473:pathology*; D016133:Polymerase Chain Reaction; D012313:RNA / Q000235:genetics; D051381:Rats; D011917:Rats, Inbred Lew; D020257:Ventricular Remodeling / Q000502:physiology*
chemical_list: D057134:Antibodies, Neutralizing; D015815:Cell Adhesion Molecules; C512836:Postn protein, rat; D012313:RNA
keywords: extracellular matrix; fibrosis; myocardial infarction; myofibroblast; periostin