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1-Adrenoceptor-Gq-RhoA signaling is
upregulated to increase myofibrillar Ca2+ sensitivity in
failing hearts
1 Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kyushu University, Maidashi 3-1-1, Higashi-ku, Fukuoka 812-8582; and 2 Department of Bioclimatology and Medicine, Medical Institute of Bioregulation, Kyushu University, Beppu 874-0838, Japan
1-Adrenergic stimulation, coupled
to Gq, has been shown to promote heart failure. However,
the role of 1-adrenergic signaling in the regulation of
myocardial contractility in failing myocardium is still poorly
understood. To investigate this, we observed 1) the effect
of phenylephrine on myofibrillar Ca2+ sensitivity in
-toxin-skinned cardiomyocytes, and 2) protein expression
of Gq, RhoA, and myosin light chain phosphorylation using
tachypacing-induced canine failing hearts. Phenylephrine significantly
increased myofibrillar Ca2+ sensitivity in failing but not
in normal cardiomyocytes. Whereas Y-27632 (Rho kinase inhibitor)
blocked the phenylephrine-induced Ca2+ sensitization in the
failing myocytes, calphostin C (protein kinase C inhibitor) had no
effect on Ca2+ sensitization. The protein
expression of Gq and RhoA and the phosphorylation level
of regulatory myosin light chain significantly increased in the failing
myocardium. Our results suggest that 1-adrenoceptor-Gq signaling is upregulated
in the failing myocardium to increase the myofibrillar Ca2+
sensitivity mainly through the RhoA-Rho kinase pathway rather than
through the protein kinase C pathway.
adrenergic agonists; cardiomyopathy; contractile proteins; G proteins; protein phosphorylation
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