Abstract
30 Mitogen-activated protein kinase (MAPK), also known as the extracellular signal regulated protein kinase (ERK), is a member of a family of serine/threonine kinases which are activated by various growth factors. To date, the expression of ERK and the nuclear dual-specificity tyrosine/threonine protein phosphatase MKP-1, a principal inactivating phosphatase of ERK1/ERK2 in many cell types, in myocardium with congestive heart failure (CHF) remain undefined. Therefore, the current study was designed to investigate ERK and MKP-1 activities in CHF patients. Cardiac tissue from normal subjects (n=5) and end-stage CHF patients (n=5) were obtained from cardiac transplantation. ERK and MKP-1 expression were determined by immunohistochemical staining (IHCS). The staining score (0-4) and positive staining area (0-100%) were determined. Both ERK and MKP-1 were expressed in nuclear and perinuclear regions of cardiomyocytes. In CHF patients, ERK phosphorylation IHCS score was significantly increased in right atrium (RA, 3.65±0.17), left atrium (LA, 3.66±0.14), right ventricle (RV, 3.72±0.11) and left ventricle (LV, 3.80±0.05) compared with normal subject RA (2.0±0.47, p<0.01), LA (1.26±0.48, p<0.01) and RV (1.02±0.37, p<0.01; normal LV tissue was not available). In contrast, MKP-1 IHCS score was significantly decreased in CHF patients (RA, 2.42±0.48; LA, 2.86±0.10; RV, 2.82±0.35; LV, 2.52±0.33) compared with normal subjects (RA, 3.92±0.04; LA, 3.75±0.10; RV, 3.77±0.06, p<0.01 vs. CHF patients). These studies first time demonstrated that ERK activity was significantly increased in human right and left atrial and ventricular myocardium with markedly decreased MKP-1 level in severe congestive heart failure. These data suggest that activation of MAPK and inhibition of MKP-1 may play a significant pathophysiological role in progression of cardiac hypertrophy and congestive heart failure.
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