p38 mitogen-activated protein kinase inhibition improves cardiac function and attenuates left ventricular remodeling following myocardial infarction in the rat

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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 α-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 β-1–stimulated collagen synthesis and α-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

Cited by (0)

Fiona See is supported by an NHMRC Dora Lush Biomedical Postgraduate Research Scholarship (Canberra, Australia). This study was partially funded by Johnson & Johnson Pharmaceutical Research & Development, L.L.C.