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Thorac Cardiovasc Surg 2011; 59(7): 386-392
DOI: 10.1055/s-0030-1250658
Original Cardiovascular

© Georg Thieme Verlag KG Stuttgart · New York

Heat Shock Protein 47 (HSP47) Antisense Oligonucleotides Reduce Cardiac Remodeling and Improve Cardiac Function in a Rat Model of Myocardial Infarction

S. Hagiwara1 , H. Iwasaka1 , C. Shingu1 , S. Matumoto1 , A. Hasegawa1 , T. Noguchi1
  • 1Department of Anesthesiology and Intensive Care Medicine, Oita University Faculty of Medicine, Yufu City, Japan
Further Information

Publication History

received April 6, 2010

Publication Date:
16 March 2011 (online)

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Abstract

Background: Cardiac remodeling after acute myocardial infarction is regulated by components of the extracellular matrix. The 47 kD heat shock protein 47 (HSP47) is a collagen-specific molecular chaperone that plays a major role during procollagen processing and/or secretion. Objective: The purpose of the study was to determine whether HSP47 inhibition can mitigate ligated left anterior descending (LAD) coronary artery-induced myocardial infarction in rats. Methods: Rats were randomly divided into four experimental groups and subjected to the following treatments: 1) intravenous (IV) administration of saline; 2) ligation of the LAD coronary artery; 3) ligation of the LAD coronary artery + IV administration of HSP47 antisense oligonucleotides; or 4) IV administration of HSP47 antisense oligonucleotides. We investigated cardiac histopathology, performed immunoblot and immunohistochemical analyses, and examined cardiac function. Results: Rats with ligated LAD coronary artery experienced upregulation of HSP47 expression, remodeling of the left ventricle, and cardiac dysfunction. In contrast, rats with ligated LAD coronary artery treated with HSP47 antisense oligonucleotides had significantly reduced HSP47 expression, cardiac remodeling, and improved cardiac function. Intravenous (IV) administration of HSP47 antisense oligonucleotides alone had no effect on cardiac morphology. Conclusion: The data strongly support the idea that changes in the extracellular matrix and its components are important determinants of cardiac remodeling after myocardial infarction.

Key words

myocardial infarction - heart disease - myocardial protection - remodeling - gene therapy - HSP47 - antisense - rat model

References

  • 1 Anversa P, Beghi C, Kikkawa Y, Olivetti G. Myocardial infarction in rats: infarct size, myocyte hypertrophy, and capillary growth.  Circ Res. 1986;  58 26-37
    PubMedSearch in Google Scholar
  • 2 Latini R, Staszewsky L, Maggioni A P Delapril Remodeling after Acute Myocardial Infarction Collaborative Group et al. Beneficial effects of angiotensin-converting enzyme inhibitor and nitrate association on left ventricular remodeling in patients with large acute myocardial infarction: the Delapril Remodeling after Acute Myocardial Infarction (DRAMI) trial.  Am Heart J. 2003;  146 133
    CrossrefPubMedSearch in Google Scholar
  • 3 Uehara K, Nomura M, Ozaki Y et al. High-sensitivity C-reactive protein and left ventricular remodeling in patients with acute myocardial infarction.  Heart Vessels. 2003;  18 67-74
    CrossrefPubMedSearch in Google Scholar
  • 4 Holmes J W, Borg T K, Covell J W. Structure and mechanics of healing myocardial infarcts.  Annu Rev Biomed Eng. 2005;  7 223-253
    CrossrefPubMedSearch in Google Scholar
  • 5 Nakai A, Satoh M, Hirayoshi K, Nagata K. Involvement of the stress protein HSP 47 in procollagen processing in the endoplasmic reticulum.  J Cell Biol. 1992;  117 903-914
    CrossrefPubMedSearch in Google Scholar
  • 6 Satoh M, Hirayoshi K, Yoshida S, Hosokawa N, Nagata K. Intracellular interaction of collagen-specific stress protein HSP 47 with newly synthesized procollagen.  J Cell Biol. 1996;  133 469-483
    CrossrefPubMedSearch in Google Scholar
  • 7 Natsume T, Koide T, Yokota S, Hirayshi K, Nagata K. Interaction between collagen-binding stress protein HSP47 and collagen.  J Biol Chem. 1994;  269 31224-31228
    PubMedSearch in Google Scholar
  • 8 Saga S, Nagata K, Chen W T, Yamada K M. pH-dependent function, purification, and intracellular location of a major collagen-binding glycoprotein.  J Cell Biol. 1987;  105 517-527
    CrossrefPubMedSearch in Google Scholar
  • 9 Nakai A, Hirayoshi K, Saga S, Yamada K M, Nagata K. The transformation-sensitive heat shock protein (HSP 47) binds specifically to feutin.  Biochem Biophys Res Commum. 1989;  169 259-264
    PubMedSearch in Google Scholar
  • 10 Masuda H, Fukumoto M, Hirayoshi K, Nagata K. Coexpression of the collagen-binding stress protein HSP47 gene and the alpha 1(I) and alpha 1(III) collagen genes in carbon tetrachloride-induced rat liver fibrosis.  J Clin Invest. 1994;  94 2481-2488
    CrossrefPubMedSearch in Google Scholar
  • 11 Razzaque M S, Taguchi T. Collagen-binding heat shock protein (HSP) 47 expression in anti-thymocyte serum (ATS)-induced glomerulonephritis.  J Pathol. 1997;  183 24-29
    CrossrefPubMedSearch in Google Scholar
  • 12 Sunamoto M, Kuze K, Iehara N et al. Expression of heat shock protein 47 is increased in remnant kidney and correlates with disease progression.  Int J Exp Pathol. 1998;  79 133-140
    PubMedSearch in Google Scholar
  • 13 Rinaldi B, Romagnoli P, Bacci S et al. Inflammatory events in a vascular remodeling model induced by surgical injury to the rat carotid artery.  Br J Pharmacol. 2006;  147 175-182
    CrossrefPubMedSearch in Google Scholar
  • 14 Agrawal S, Temsamani J, Tang J Y. Phamacokinetics, biodistribution, and stability of oligodeoxynucleotide phosphorothioates in mice.  Proc Natl Acad Sci USA. 1991;  88 7595-7599
    CrossrefPubMedSearch in Google Scholar
  • 15 Woessner J F. The determination of hydroxyproline in tissue and protein samples containing small proportions of this amino acid.  Arch Biochem Biophys. 1961;  93 440-447
    CrossrefPubMedSearch in Google Scholar
  • 16 Hagiwara S, Iwasaka H, Uchino T, Noguchi T. High mobility group box 1 induces a negative inotropic effect on the left ventricle in an isolated rat heart model of septic shock: a pilot study.  Circ J. 2008;  72 1012-1017
    CrossrefPubMedSearch in Google Scholar
  • 17 McKay R G, Pfeffer M A, Pasternak R C et al. Left ventricular remodeling after myocardial infarction: a corollary to infarct expansion.  Circulation. 1986;  74 693-702
    CrossrefPubMedSearch in Google Scholar
  • 18 Spinale F G. Myocardial matrix remodeling and the matrix metalloproteinases: influence on cardiac form and function.  Physiol Rev. 2007;  87 1285-1342
    CrossrefPubMedSearch in Google Scholar
  • 19 Pfeffer M A, Braunwald E. Ventricular remodeling after myocardial infarction: experimental observations and clinical implications.  Circulation. 1990;  81 1161-1172
    CrossrefPubMedSearch in Google Scholar
  • 20 Nagata K. Expression and function of heat shock protein 47: a collagen-specific molecular chaperone in the endoplasmic reticulum.  Matrix Biol. 1998;  16 379-386
    CrossrefPubMedSearch in Google Scholar
  • 21 Nagata K. HSP 47: a collagen-specific molecular chaperone.  Trends Biochem Sci. 1996;  21 23-26
    PubMedSearch in Google Scholar
  • 22 Sauk J J, Smith T, Norris K, Ferreira L. Hsp47 and the translation-translocation machinery cooperate in the production of alpha 1(I) chains of type I procollagen.  J Biol Chem. 1994;  269 3941-3946
    PubMedSearch in Google Scholar
  • 23 Gallagher G L, Jackson C J, Hunyor S N. Myocardial extracellular matrix remodeling in ischemic heart failure.  Front Biosci. 2007;  12 1410-1419
    CrossrefPubMedSearch in Google Scholar
  • 25 Hagiwara S, Iwasaka H, Matsumoto S, Noguchi T. A antisense oligonucleotide to HSP47 inhibits paraquat-induced pulmonary fibrosis in rats.  Toxicology. 2007;  236 199-207
    CrossrefPubMedSearch in Google Scholar
  • 26 Hagiwara S, Iwasaka H, Matsumoto S, Noguchi T. Antisense oligonucleotide inhibition of heat shock protein (HSP) 47 improves bleomycin-induced pulmonary fibrosis in rats.  Respir Res. 2007;  8 37
    CrossrefPubMedSearch in Google Scholar
  • 27 Hagiwara S, Iwasaka H, Matsumoto S, Noguchi T. Introduction of antisense oligonucleotides to heat shock protein 47 prevents pulmonary fibrosis in lipopolysaccharide-induced pneumopathy of the rat.  Eur J Pharmacol. 2007;  564 174-180
    CrossrefPubMedSearch in Google Scholar
  • 28 van den Borne S W, Diez J, Blankesteijn W M, Verjans J, Hofstra L, Narula J. Myocardial remodeling after infarction: the role of myofibroblasts.  Nat Rev Cardiol. 2010;  7 30-37
    CrossrefPubMedSearch in Google Scholar

Dr. Satoshi Hagiwara, MD, PhD

Department of Anesthesiology and Intensive Care Medicine
Oita University Faculty of Medicine

1-1 Idaigaoka-Hasamamachi

8795593 Yufu City

Japan

Phone: +81 9 75 86 59 43

Fax: +81 9 75 86 59 49

Email: saku@med.oita-u.ac.jp