© 2000 American Heart Association, Inc.
Cellular Biology |
Signaling Properties and Functions of Two Distinct Cardiomyocyte Protease-Activated Receptors
From the Departments of Pharmacology (A.S., G.M., H.Z., E.P., S.F.S.) and Medicine (S.F.S.), Columbia University, New York, NY, and the R.W. Johnson Pharmaceutical Research Institute (A.D., P.A.-G.), Spring House, Pa.
Correspondence to Susan F. Steinberg, MD, Associate Professor of Pharmacology and Medicine, Department of Pharmacology, College of Physicians and Surgeons, Columbia University, 630 W 168 St, New York, NY 10032. E-mail sfs1{at}columbia.edu
Abstract—Previous studies have
established that cardiomyocytes express
protease-activated receptor (PAR)-1, a high-affinity receptor
for thrombin, which is also activated by the tethered-ligand
domain sequence (SFLLRN) and which promotes inositol trisphosphate
accumulation, stimulates extracellular signal–regulated protein
kinase, and modulates contractile function. A single previous report
identified PAR-1 as a hypertrophic stimulus, but there have been no
subsequent investigations of the mechanism. This study reveals the
coexpression of PAR-1 and PAR-2 (a second PAR, which is
activated by trypsin/tryptase but not thrombin) by Northern
blot analysis and compares their signaling properties in
neonatal rat ventricular cardiomyocytes. SFLLRN
and SLIGRL (an agonist peptide for PAR-2) promote inositol
trisphosphate accumulation, stimulate mitogen-activated protein
kinases (extracellular signal–regulated protein kinase and
p38-mitogen-activated protein kinase), elevate calcium
concentration, and increase spontaneous automaticity. SFLLRN (but not
SLIGRL) also activates c-Jun NH2-terminal kinase
and AKT. In keeping with their linkage to pathways that have
been associated with growth and/or survival, SFLLRN and SLIGRL both
induce hypertrophy. However, PAR agonists promote cell
elongation, a morphology that is distinct from the uniform increase in
cell dimension induced by 
1-adrenergic receptor
activation. These studies provide novel evidence that
cardiomyocytes coexpress 2 functional PARs, which link to a
common set of signals that culminate in changes in contractile function
and hypertrophic growth. PAR actions may assume clinical importance in
the border zone surrounding an infarction, where local proteolysis of
PARs by serine proteases generated during inflammatory or thrombogenic
pathways would elevate calcium concentration (setting the stage for
arrhythmias), promote hypertrophic growth, and/or influence
cardiomyocyte survival.
Key Words: thrombin • inositol trisphosphate • mitogen-activated protein kinases • Ca2+ • hypertrophy
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