• Open Access

PKCβII inhibition attenuates myocardial infarction induced heart failure and is associated with a reduction of fibrosis and pro-inflammatory responses

Authors

  • Suresh Selvaraj Palaniyandi,

    1. Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, CA, USA
    Search for more papers by this author
    • These authors contributed equally to the study.

  • Julio Cesar Batista Ferreira,

    1. Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, CA, USA
    2. School of Physical Education and Sport, University of São Paulo, São Paulo, Brazil
    Search for more papers by this author
    • These authors contributed equally to the study.

  • Patricia Chakur Brum,

    1. School of Physical Education and Sport, University of São Paulo, São Paulo, Brazil
    Search for more papers by this author
  • Daria Mochly-Rosen

    Corresponding author
    1. Department of Chemical and Systems Biology, Stanford University School of Medicine, Stanford, CA, USA
    Search for more papers by this author

Daria MOCHLY-ROSEN, Department of Chemical and Systems Biology, Stanford University School of Medicine, CCSR, Room 3145A, 269 Campus Drive, Stanford, CA 94305-5174, USA. Tel.: +1-650-725-7720 Fax: +1-650-723-2253 E-mail: mochly@stanford.edu

Abstract

Protein kinase C βII (PKCβII) levels increase in the myocardium of patients with end-stage heart failure (HF). Also targeted overexpression of PKCβII in the myocardium of mice leads to dilated cardiomyopathy associated with inflammation, fibrosis and myocardial dysfunction. These reports suggest a deleterious role of PKCβII in HF development. Using a post-myocardial infarction (MI) model of HF in rats, we determined the benefit of chronic inhibition of PKCβII on the progression of HF over a period of 6 weeks after the onset of symptoms and the cellular basis for these effects. Four weeks after MI, rats with HF signs that were treated for 6 weeks with the PKCβII selective inhibitor (βIIV5-3 conjugated to TAT47–57 carrier peptide) (3 mg/kg/day) showed improved fractional shortening (from 21% to 35%) compared to control (TAT47–57 carrier peptide alone). Formalin-fixed mid-ventricle tissue sections stained with picrosirius red, haematoxylin and eosin and toluidine blue dyes exhibited a 150% decrease in collagen deposition, a two-fold decrease in inflammation and a 30% reduction in mast cell degranulation, respectively, in rat hearts treated with the selective PKCβII inhibitor. Further, a 90% decrease in active TGFβ1 and a significant reduction in SMAD2/3 phosphorylation indicated that the selective inhibition of PKCβII attenuates cardiac remodelling mediated by the TGF-SMAD signalling pathway. Therefore, sustained selective inhibition of PKCβII in a post-MI HF rat model improves cardiac function and is associated with inhibition of pathological myocardial remodelling.

Ancillary