Cardioprotective Effect of Endogenous Pituitary Adenylate Cyclase-Activating Polypeptide on Doxorubicin-Induced Cardiomyopathy in Mice

• Mori Hiroyoshi

  Division of Cardiology, Department of Internal Medicine, Showa University Fujigaoka Hospital Department of First Anatomy, Showa University School of Medicine

• Nakamachi Tomoya

  Department of First Anatomy, Showa University School of Medicine Center for Biotechnology, Showa University

• Ohtaki Hirokazu

  Department of First Anatomy, Showa University School of Medicine

• Yofu Sachiko

  Department of First Anatomy, Showa University School of Medicine

• Sato Atsushi

  Department of First Anatomy, Showa University School of Medicine

• Endo Kimi

  Department of First Anatomy, Showa University School of Medicine

• Iso Yoshitaka

  Division of Cardiology, Department of Internal Medicine, Showa University Fujigaoka Hospital

• Suzuki Hiroshi

  Division of Cardiology, Department of Internal Medicine, Showa University Fujigaoka Hospital

• Takeyama Youichi

  Division of Cardiology, Department of Internal Medicine, Showa University Fujigaoka Hospital

• Shintani Norihito

  Laboratory of Molecular Neuropharmacology, Graduate School of Pharmaceutical Sciences, Osaka University

• Hashimoto Hitoshi

  Laboratory of Molecular Neuropharmacology, Graduate School of Pharmaceutical Sciences, Osaka University

• Baba Akemichi

  Laboratory of Molecular Neuropharmacology, Graduate School of Pharmaceutical Sciences, Osaka University

• Shioda Seiji

  Department of First Anatomy, Showa University School of Medicine

Abstract

Background: Pituitary adenylate cyclase-activating polypeptide (PACAP) is known as a cytoprotective polypeptide. PACAP and its receptors are expressed in the heart, but it is unclear whether PACAP exerts its protective effect on the myocardium in vivo. The aim of the present study was to investigate whether endogenous PACAP has a cardioprotective effect on Doxorubicin (Dox)-induced cardiomyopathy. Methods and Results: Dox was intraperitoneally injected to induce cardiomyopathy in wild type (WT) and PACAP knockout (ie, PACAP+/- and PACAP-/-) mice. The survival rates up to 15 days of PACAP+/- mice and PACAP-/- mice were significantly less than that of WT mice. Cardiac function, measured by echocardiography, was significantly lower in PACAP+/- mice than in WT mice at day 10. Morphological examination of sections of myocardium showed degenerative change and fibrosis in PACAP+/- mice at day 10. Serum reactive oxygen metabolites (a marker of oxidative stress), the number of 8-hydroxy-deoxyguanosine-positive nuclei and TdT-mediated dUTP nick end-labeling (TUNEL) positive nuclei in the myocardium were higher in PACAP+/- mice than WT mice. However, continuous subcutaneous administration of PACAP38 was able to prevent the myocardial damage typically caused by Dox injection in PACAP+/-. Conclusions: These results suggest that endogenous PACAP might attenuate Dox-induced myocardial damage and that its mechanism of action is likely to be associated with the reduction of oxidative stress and mediated via anti-apoptotic effects.  (Circ J 2010; 74: 1183 - 1190)<br>

Journal

• Circulation Journal

  Circulation Journal 74 (6), 1183-1190, 2010

  The Japanese Circulation Society

Keywords

• Apoptosis
• Cardiomyopathy
• Heart failure
• Oxidative stress
• PACAP

Details

• CRID: 1390282680082398208
• NII Article ID: 10026474818
• NII Book ID: AA11591968
• DOI: 10.1253/circj.cj-09-1024
• ISSN: 13474820
• ISSN: 13469843
• Web Site: http://www.jstage.jst.go.jp/article/circj/74/6/74_CJ-09-1024/_pdf
• Web Site: https://search.jamas.or.jp/link/ui/2010310548
• Text Lang: en
• Data Source:
  • JaLC
  • Crossref
  • CiNii Articles
• Abstract License Flag: Disallowed