Alpha1-adrenoceptor-Gq-RhoA signaling is upregulated to increase myofibrillar Ca2+ sensitivity in failing hearts.
Alpha1-adrenergic stimulation, coupled to Gq, has been shown to promote heart failure. However, the role of alpha1-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 alpha-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 Galpha(q) and RhoA and the phosphorylation level of regulatory myosin light chain significantly increased in the failing myocardium. Our results suggest that alpha1-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.
Suematsu
N
N
Department of Cardiovascular Medicine, Graduate School of Medical Sciences, Kyushu University, Maidashi 3-1-1, Higashi-ku, Fukuoka 812-8582, Japan.
Satoh
S
S
Kinugawa
S
S
Tsutsui
H
H
Hayashidani
S
S
Nakamura
R
R
Egashira
K
K
Makino
N
N
Takeshita
A
A
D000577:Amides / Q000494:pharmacology; D000818:Animals; D002118:Calcium / Q000502:physiology*; D004285:Dogs; D004791:Enzyme Inhibitors / Q000494:pharmacology; D019204:GTP-Binding Proteins / Q000502:physiology; D006321:Heart / Q000503:physiopathology; D006333:Heart Failure / Q000503:physiopathology*; D009200:Myocardial Contraction; D010766:Phosphorylation; D011725:Pyridines / Q000494:pharmacology; D018340:Receptors, Adrenergic, alpha-1 / Q000502:physiology; D015398:Signal Transduction; D020742:rhoA GTP-Binding Protein / Q000502:physiology
D000577:Amides; D004791:Enzyme Inhibitors; D011725:Pyridines; D018340:Receptors, Adrenergic, alpha-1; C108830:Y 27632; D019204:GTP-Binding Proteins; D020742:rhoA GTP-Binding Protein; D002118:Calcium