TY - JOUR
T1 - α1-adrenoceptor-Gq-RhoA signaling is upregulated to increase myofibrillar Ca2+ sensitivity in failing hearts
AU - Suematsu, Nobuhiro
AU - Satoh, Shinji
AU - Kinugawa, Shintaro
AU - Tsutsui, Hiroyuki
AU - Hayashidani, Shunji
AU - Nakamura, Ryo
AU - Egashira, Kensuke
AU - Makino, Naoki
AU - Takeshita, Akira
PY - 2001
Y1 - 2001
N2 - α1-Adrenergic stimulation, coupled to Gq, has been shown to promote heart failure. However, the role of α1-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 α-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 Gαq and RhoA and the phosphorylation level of regulatory myosin light chain significantly increased in the failing myocardium. Our results suggest that α1-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.
AB - α1-Adrenergic stimulation, coupled to Gq, has been shown to promote heart failure. However, the role of α1-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 α-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 Gαq and RhoA and the phosphorylation level of regulatory myosin light chain significantly increased in the failing myocardium. Our results suggest that α1-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.
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U2 - 10.1152/ajpheart.2001.281.2.h637
DO - 10.1152/ajpheart.2001.281.2.h637
M3 - Article
C2 - 11454567
AN - SCOPUS:0034886037
SN - 0363-6135
VL - 281
SP - H637-H646
JO - American Journal of Physiology - Heart and Circulatory Physiology
JF - American Journal of Physiology - Heart and Circulatory Physiology
IS - 2 50-2
ER -