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 ,
Kerrie Way, PhD ,
Alex Tzanidis, PhD*,
Andrew Kompa, PhD*,
Dion Lewis*,
Silviu Itescu, MBBS (Hons), FRACP 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
Baker Heart Institute, Melbourne, Australia
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  -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 -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.
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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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