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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, 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

View larger version (18K): [in a new window]   Figure 1 Percentage changes in echocardiographic parameters in each group over the treatment period. (a) Percentage change in fractional shortening. (b) Percentage change in infarct size (%) in MI treatment groups. (c) Percentage change in LV internal dimensions in diastole (LVIDd) (mm). (d) Percentage change in LV internal dimensions in systole (LVIDs) (mm). *p < 0.05 versus shams. p < 0.05 versus MI+V. White bars = shams; black bars = MI+V; hatched bars = MI+RWJ-67657.

View larger version (131K): [in a new window]   Figure 2 Immunolocalization of fibrillar collagen type I by a three-layer immunoperoxidase technique. Sham-operated animals demonstrated constitutive collagen type I expression throughout the myocardium (a). In contrast, myocardium from vehicle-treated myocardial infarction (MI) animals demonstrated increased deposition of collagen type I in both the non-infarct and peri-infarct zones (b,d) and in the infarct regions (f). The MI animals treated with RWJ-67657 demonstrated less collagen type I immunoreactivity in each region compared with vehicle-treated MI animals (c, e, g). (Magnification: x200.)

View larger version (35K): [in a new window]   Figure 3 Percentage area of myocardium in the non-infarct zone, peri-infarct zone, and infarct zone stained positive for collagen type I (a) and collagen type III (b) in each group. Percentage immunoreactivity was assessed as a repeat measure in five random fields in each region. Data are represented as mean ± SEM. n = 8. *p < 0.05 versus shams. p < 0.05 versus MI+V. White bars = shams; black bars = MI+V; hatched bars = MI+RWJ-67657.

View larger version (123K): [in a new window]   Figure 4 Immunolocalization of fibrillar collagen type III by a three-layer immunoperoxidase technique. Sham-operated animals demonstrated constitutive collagen type III expression throughout the myocardium (a). In contrast, myocardium from myocardial infarction (MI) animals demonstrated increased deposition of collagen type III in both the non-infarct and peri-infarct regions (b,d) and in the infarct region (f). The MI animals treated with RWJ-67657 demonstrated similar extents of collagen type III distribution compared with vehicle-treated MI animals (c, e, g). (Magnification: x200).

View larger version (19K): [in a new window]   Figure 5 Fold increases in -smooth muscle actin (SMA) expression in the infarct zone (a) and non-infarcted myocardium (b) compared with sham-operated hearts. Representative Western blots are shown. n = 6 per group. *p < 0.05 versus shams. p < 0.05 versus MI+V. White bars = shams; black bars = MI+V; hatched bars = MI+RWJ-67657.

View larger version (23K): [in a new window]   Figure 6 Relative myocyte cross-sectional areas in the non-infarct and peri-infarct zones compared with shams. n = 6 per group. *p < 0.05 versus shams. p < 0.05 versus MI+V. White bars = shams; black bars = MI+V; hatched bars = MI+RWJ-67657.

View larger version (19K): [in a new window]   Figure 7 (a) 3H-proline incorporation, an estimate of collagen synthesis, by neonatal rat cardiac fibroblasts cultured in the presence of TGF-ß1 and various concentrations of RWJ. (b) Northern blot analyses of 1(I) procollagen gene expression relative to the housekeeping gene, GAPDH, in neonatal rat cardiac fibroblasts cultured in the presence of RWJ and TGF-ß1. n = 3 for each condition. Data are represented as mean ± SEM. *p < 0.05 versus unstimulated. p <0.05 versus TGF-ß1 stimulation alone.

View larger version (19K): [in a new window]   Figure 8 Fold increases in -smooth muscle actin expression compared with unstimulated neonatal rat cardiac fibroblasts. n = 3 per condition. Data are from three separate experiments. Representative Western blots are shown. *p < 0.05 versus unstimulated. p < 0.05 versus TGF-ß1.

View larger version (12K): [in a new window]   Figure 9 Myocyte apoptosis induced by hydrogen peroxide assessed by percentage of TUNEL-positive myocytes in culture. n = 3 per group. Data are from three separate experiments. *p < 0.05 versus unstimulated. p < 0.05 versus TGF-ß1.

View larger version (71K): [in a new window]   Figure 10 (Top panel) Representative Western blots for phosphorylated and total p38 MAPK expression and (bottom panel) phosphorylated and total ERK1/2 expression in neonatal rat cardiac myocytes infected with an adenovirus coding for the rat angiotensin type I receptor. AngII = angiotensin II; RWJ = RWJ-67657.