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J Am Coll Cardiol, 2004; 44:1679-1689, doi:10.1016/j.jacc.2004.07.038
© 2004 by the American College of Cardiology Foundation
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p38 mitogen-activated protein kinase inhibition improves cardiac function and attenuates left ventricular remodeling following myocardial infarction in the rat

Fiona See, BSc (Hons)*, Walter Thomas, PhD{dagger}, Kerrie Way, PhD{ddagger}, Alex Tzanidis, PhD*, Andrew Kompa, PhD*, Dion Lewis*, Silviu Itescu, MBBS (Hons), FRACP{ddagger} and Henry Krum, MBBS, PhD, FRACP*,*

* National Health and Medical Research Council Center of Clinical Research Excellencein Therapeutics, Department of Medicine, Monash University, Alfred Hospital, Melbourne, Australia
{dagger} Baker Heart Institute, Melbourne, Australia
{ddagger} Adult Stem Cell Biology and Cardiovascular Disease Group, Department of Medicine, University of Melbourne, Melbourne, Australia

Manuscript received April 19, 2004; revised manuscript received June 23, 2004, accepted July 19, 2004.

* Reprint requests and correspondence: Prof. Henry Krum, NHMRC CCREin Therapeutics, Department of Medicine, Monash Medical School University, Alfred Hospital, Commercial Road, Prahran Victoria 3181, Australia (Email: henry.krum{at}med.monash.edu.au).

OBJECTIVES: The aim of this study was to examine the effect of the p38 mitogen-activated protein kinase (MAPK) inhibitor, RWJ-67657 (RWJ), on left ventricular (LV) dysfunction and remodeling post-myocardial infarction (MI) in rats.

BACKGROUND: p38 MAPK signaling has been implicated in the progression of chronic heart failure.

METHODS: From day 7 post-MI (coronary artery ligation), rats received either RWJ (50 mg/day, by gavage, n = 8, MI+RWJ) or vehicle (by gavage, n = 8, MI+V) for 21 days. Echocardiography was performed on day 6, before the commencement of treatment, and on day 27. In vivo hemodynamic measurements were made on day 28. Sham-operated rats served as controls.

RESULTS: The LV end-diastolic pressure and lung/body weight ratio were reduced, whereas the maximum rate of rise of LV pressure was increased towards sham levels in MI+RWJ compared with MI+V. Baseline echocardiographic studies demonstrated uniform LV remodeling and dysfunction in MI rats. Fractional shortening (FS) further deteriorated in MI+V, whereas FS was preserved in MI+RWJ. Progressive LV dilation and infarct expansion observed in MI+V were inhibited in MI+RWJ. MI+RWJ also demonstrated increased myocyte hypertrophy in the peri-infarct and non-infarct zones, and reduced myocardial collagen and {alpha}-smooth muscle actin (SMA) immunoreactivity compared with MI+V. The antifibrotic effects of RWJ in vivo may reflect direct effects on cardiac fibroblasts, because RWJ attenuated transforming growth factor ß-1–stimulated collagen synthesis and {alpha}-SMA expression in isolated cardiac fibroblasts. RWJ also protected cultured myocytes from hydrogen peroxide-induced apoptosis.

CONCLUSIONS: RWJ-67657 treatment post-MI had beneficial effects on LV remodeling and dysfunction, supporting a key role for p38 MAPK in pathologic cell signaling in these processes and its inhibition as a novel therapy.

Abbreviations and Acronyms
  AngII = angiotensin II
  DMEM = Dulbecco's modified Eagle medium
  +dP/dtmax = maximum rate of rise of left ventricular pressure
  ERK = extracellular signal regulated protein kinase
  FS = fractional shortening
  LV = left ventricle/ventricular
  LVEDP = left ventricular end-diastolic pressure
  MAPK = mitogen-activated protein kinase
  MI = myocardial infarction
  RWJ = RWJ-67657
  SMA = smooth muscle actin
  TGF = transforming growth factor
  TUNEL = terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end labeling




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