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

• Published in: Journal of the American College of Cardiology Vol. 44; no. 8; pp. 1679 - 1689
• Main Authors: See, Fiona, Thomas, Walter, Way, Kerrie, Tzanidis, Alex, Kompa, Andrew, Lewis, Dion, Itescu, Silviu, Krum, Henry
• Format: Journal Article
• Language: English
• Published: New York, NY Elsevier Inc 19.10.2004; Elsevier Science; Elsevier Limited
• Subjects: Animals; Apoptosis - drug effects; Apoptosis - physiology; Biological and medical sciences; Cardiology; Cardiology. Vascular system; Cells, Cultured; Collagen Type I - metabolism; Collagen Type II - metabolism; Coronary heart disease; Disease; Echocardiography; Enzyme Inhibitors - pharmacology; Female; Gene expression; Heart; Heart attacks; Heart failure; Hemodynamics - drug effects; Hemodynamics - physiology; Imidazoles - pharmacology; Immunoenzyme Techniques; Kinases; Medical sciences; Myocardial Contraction - drug effects; Myocardial Contraction - physiology; Myocardial Infarction - pathology; Myocardial Infarction - physiopathology; Myocarditis. Cardiomyopathies; Myocardium - pathology; Myocytes, Cardiac - drug effects; Myocytes, Cardiac - pathology; Myocytes, Cardiac - physiology; p38 Mitogen-Activated Protein Kinases - antagonists & inhibitors; p38 Mitogen-Activated Protein Kinases - physiology; Pharmaceuticals; Proteins; Pyridines - pharmacology; R&D; Rats; Rats, Sprague-Dawley; Research & development; Rodents; Signal Transduction - drug effects; Signal Transduction - physiology; Studies; Surgery; Veins & arteries; Ventricular Dysfunction, Left - pathology; Ventricular Dysfunction, Left - physiopathology; Ventricular Remodeling - drug effects; Ventricular Remodeling - physiology; dP/dtmax; RWJ; SMA; LV; MAPK; FS; LVEDP; DMEM; TGF; TUNEL; MI; AngII; ERK; Heart; Myocardial infarction; Rat; Enzyme; Rodentia; Mitogen-activated protein kinase; Cardiovascular disease; Myocardial disease; Vascular remodeling; Vertebrata; Mammalia; Treatment; Heart disease; Animal; Inhibition; Left ventricle performance
• ISSN: 0735-1097; 1558-3597
• DOI: 10.1016/j.jacc.2004.07.038

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