Cardiac-specific transgenic overexpression of α1B-adrenergic receptors induce chronic activation of ERK MAPK signalling

Abstract

Cardiomyocyte-specific overexpression of the wild-type α1B-adrenergic receptor (α1B-AR) produces a slowly progressing cardiomyopathy associated with clinical signs of heart failure and premature death around middle age (Lemire et al. 2001). In the heart, α1-AR activate the extracellular signal-regulated kinase (ERK) MAPK cascade. The aim of this project was to determine if cardiac-specific overexpression of the wild-type α1B-AR results in sustained activation of the ERK pathway. At 3 and 9 months, ERK activity was increased in α1B-AR overexpressing hearts relative to non-transgenic animals. Similarly, phosphorylation of MEK and p90rskwere also elevated. MAP kinase phosphatases (MKPs), which inactivate MAP kinases, are transcriptionally regulated. MKP2 mRNA levels were reduced at 3 months in α1B-AR overexpressing hearts. Interestingly, there was a general trend for reduced expression of MKP-1, -2, and -3 with increased age. In addition, expression of the modulatory calcineurin-interacting protein (MCIP) 1, an indicator of calcineurin activity, was elevated 3-fold in α1B-AR overexpressing hearts at both 3 and 9 months. These results indicate that the overexpression of the wild-type α1B-AR leads to chronic changes in the activation of signalling pathways previously shown to be associated with the hypertrophic response.Key words: cell communication, adrenergic receptor, signal transduction, heart, ERK, MKP, MCIP1.