Increased ERK activation and decreased MKP-1 expression in human myocardium with congestive heart failure

Abstract

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 activity 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 human myocardium with congestive heart failure (CHF) remain undefined. Therefore, the current study was designed to investigate ERK and MKP-1 expression in CHF patients. Cardiac tissue from normal subjects (n = 5) and end-stage CHF patients (n = 5) were obtained during 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 and positive staining area were significantly increased in right atrium (RA), left atrium (LA), right ventricle (RV), and left ventricle (LV) compared with normal subject RA, LA, and RV (normal LV tissue was not available). In contrast, MKP-1 IHCS score and positive staining area were significantly decreased in CHF patients RA, LA, RV, and LV myocardium compared with normal subjects. The cardiomyocyte diameter determined by BioQuant system was significantly increased in CHF myocardium compared with normal subjects. These studies suggest that activation of ERK and inhibition of MKP-1 may play a significant pathophysiological role in progression of cardiac hypertrophy and congestive heart failure.