© 1995 American Heart Association, Inc.
Articles |
Activation of Mitogen-Activated Protein Kinase in Porcine Carotid Arteries
From the Departments of Medicine, Physiology and Biophysics, and the Krannert Institute of Cardiology, Indiana University School of Medicine, Indianapolis.
Correspondence to Dr Leonard P. Adam, Krannert Institute of Cardiology, 1111 W 10th St, Indianapolis, IN 46202-4800.
Abstract The thin-filament protein h-caldesmon (the high molecular weight isoform of caldesmon) is phosphorylated in resting and contracted porcine carotid arteries. Phosphorylation of h-caldesmon in intact tissue occurs at sites that are covalently modified by mitogen-activated protein kinase (MAPK) in vitro. In this study, we have evaluated MAPK activation in arteries in response to mechanical load and pharmacological stimulation. MAPK was extracted from resting and stimulated porcine carotid arteries and then partially purified by anion-exchange fast-performance liquid chromatography. MAPK activity was separated into two peaks corresponding to the tyrosine-phosphorylated 42- and 44-kD isoforms of MAPK (p42MAPK and p44MAPK, respectively). Of the total MAPK activity, 42% was associated with p42MAPK, and 58% was associated with p44MAPK; this percentage was not altered by stimulation of the muscles with either KCl (110 mmol/L) or phorbol 12,13-dibutyrate (PDBu, 1 µmol/L). Both p42MAPK and p44MAPK, purified from porcine carotid arteries, phosphorylated h-caldesmon at the same sites and to levels approaching or >1 mol phosphate per mole protein. In unloaded muscle strips, MAPK activity was 39 pmol · min-1 · mg protein-1 when assayed with the peptide substrate APRTPGGRR. MAPK activity increased in response to incremental mechanical loading to a maximum of 99 pmol · min-1 · mg protein-1 at 16x103 N/m2. MAPK activity could be further increased in loaded muscles by pharmacological stimulation. With KCl stimulation, MAPK activities rose to a peak of 205 pmol · min-1 · mg protein-1 at 10 minutes and then declined to basal values at 30 and 60 minutes. Stimulation with PDBu induced a gradual increase in MAPK activity that reached a value of 201 pmol · min-1 · mg protein-1 at 60 minutes. These results demonstrate that the level of MAPK activity in vascular smooth muscle is regulated in response to both mechanical load and pharmacological stimulation. Activation of MAPK and the subsequent phosphorylation of h-caldesmon may be important processes that modulate vascular smooth muscle contractility.
Key Words: smooth muscle • mitogen-activated protein kinase • contraction • signal transduction • caldesmon
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