Cardiac-specific transgenic overexpression of alpha1B-adrenergic receptors induce chronic activation of ERK MAPK signalling.
Cardiomyocyte-specific overexpression of the wild-type alpha(1B)-adrenergic receptor (alpha(1B)-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, alpha(1)-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 alpha(1B)-AR results in sustained activation of the ERK pathway. At 3 and 9 months, ERK activity was increased in alpha(1B)-AR overexpressing hearts relative to non-transgenic animals. Similarly, phosphorylation of MEK and p90(rsk) were also elevated. MAP kinase phosphatases (MKPs), which inactivate MAP kinases, are transcriptionally regulated. MKP2 mRNA levels were reduced at 3 months in alpha(1B)-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 alpha(1B)-AR overexpressing hearts at both 3 and 9 months. These results indicate that the overexpression of the wild-type alpha(1B)-AR leads to chronic changes in the activation of signalling pathways previously shown to be associated with the hypertrophic response.
Benoit
Marie-Josée
MJ
Department of Biochemistry, Université de Montréal, Montréal, QC H3C 3J7, Canada.
Rindt
Hansjörg
H
Allen
Bruce G
BG
D000367:Age Factors; D000818:Animals; D004268:DNA-Binding Proteins; D004789:Enzyme Activation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins; D020935:MAP Kinase Signaling System; D051379:Mice; D008822:Mice, Transgenic; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D009124:Muscle Proteins / Q000378:metabolism; D009206:Myocardium / Q000201:enzymology* / Q000378:metabolism; D010749:Phosphoprotein Phosphatases / Q000378:metabolism; D018340:Receptors, Adrenergic, alpha-1 / Q000235:genetics / Q000378:metabolism*; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000378:metabolism
C547716:ADRA1B protein, human; C547717:Adra1b protein, mouse; D004268:DNA-Binding Proteins; D047908:Intracellular Signaling Peptides and Proteins; D009124:Muscle Proteins; C108612:RCAN1 protein, human; D018340:Receptors, Adrenergic, alpha-1; D038744:Ribosomal Protein S6 Kinases, 90-kDa; D048049:Extracellular Signal-Regulated MAP Kinases; D020929:Mitogen-Activated Protein Kinase Kinases; D010749:Phosphoprotein Phosphatases