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p38 mitogen-activated protein kinase inhibition improves cardiac function and attenuates left ventricular remodeling following myocardial infarction in the rat.
J Am Coll Cardiol. 2004 Oct 19; 44(8):1679-89.JACC

Abstract

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 beta-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.

Authors+Show Affiliations

National Health and Medical Research Council Center of Clinical Research Excellence in Therapeutics, Department of Medicine, Monash University, Alfred Hospital, Commercial Road, Prahran, Victoria 3181, Australia.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

15489104

Citation

See, Fiona, et al. "P38 Mitogen-activated Protein Kinase Inhibition Improves Cardiac Function and Attenuates Left Ventricular Remodeling Following Myocardial Infarction in the Rat." Journal of the American College of Cardiology, vol. 44, no. 8, 2004, pp. 1679-89.
See F, Thomas W, Way K, et al. P38 mitogen-activated protein kinase inhibition improves cardiac function and attenuates left ventricular remodeling following myocardial infarction in the rat. J Am Coll Cardiol. 2004;44(8):1679-89.
See, F., Thomas, W., Way, K., Tzanidis, A., Kompa, A., Lewis, D., Itescu, S., & Krum, H. (2004). P38 mitogen-activated protein kinase inhibition improves cardiac function and attenuates left ventricular remodeling following myocardial infarction in the rat. Journal of the American College of Cardiology, 44(8), 1679-89.
See F, et al. P38 Mitogen-activated Protein Kinase Inhibition Improves Cardiac Function and Attenuates Left Ventricular Remodeling Following Myocardial Infarction in the Rat. J Am Coll Cardiol. 2004 Oct 19;44(8):1679-89. PubMed PMID: 15489104.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - p38 mitogen-activated protein kinase inhibition improves cardiac function and attenuates left ventricular remodeling following myocardial infarction in the rat. AU - See,Fiona, AU - Thomas,Walter, AU - Way,Kerrie, AU - Tzanidis,Alex, AU - Kompa,Andrew, AU - Lewis,Dion, AU - Itescu,Silviu, AU - Krum,Henry, PY - 2004/04/19/received PY - 2004/06/23/revised PY - 2004/07/19/accepted PY - 2004/10/19/pubmed PY - 2004/12/16/medline PY - 2004/10/19/entrez SP - 1679 EP - 89 JF - Journal of the American College of Cardiology JO - J Am Coll Cardiol VL - 44 IS - 8 N2 - 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 beta-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. SN - 0735-1097 UR - https://www.unboundmedicine.com/medline/citation/15489104/p38_mitogen_activated_protein_kinase_inhibition_improves_cardiac_function_and_attenuates_left_ventricular_remodeling_following_myocardial_infarction_in_the_rat_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0735-1097(04)01537-2 DB - PRIME DP - Unbound Medicine ER -