Disruption of Epac1 protects the heart from adenylyl cyclase type 5-mediated cardiac dysfunction.
Type 5 adenylyl cyclase (AC5) plays an important role in the development of chronic catecholamine stress-induced heart failure and arrhythmia in mice. Epac (exchange protein activated by cAMP), which is directly activated by cAMP independent of protein kinase A, has been recently identified as a novel mediator of cAMP signaling in the heart. However, the role of Epac in AC5-mediated cardiac dysfunction and arrhythmias remains poorly understood. We therefore generated AC5 transgenic mice (AC5TG) with selective disruption of the Epac1 gene (AC5TG-Epac1KO), and compared their phenotypes with those of AC5TG after chronic isoproterenol (ISO) infusion. Decreased cardiac function as well as increased susceptibility to pacing-induced atrial fibrillation (AF) in response to ISO were significantly attenuated in AC5TG-Epac1KO mice, compared to AC5TG mice. Increased cardiac apoptosis and cardiac fibrosis were also concomitantly attenuated in AC5TG-Epac1KO mice compared to AC5TG mice. These findings indicate that Epac1 plays an important role in AC5-mediated cardiac dysfunction and AF susceptibility.
Cardiovascular Research Institute, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
Wenqian
W
Cai
Cardiovascular Research Institute, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
Takayuki
T
Fujita
Cardiovascular Research Institute, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
Yuko
Y
Hidaka
Cardiovascular Research Institute, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
Huiling
H
Jin
Cardiovascular Research Institute, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
Kenji
K
Suita
Cardiovascular Research Institute, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
Rajesh
R
Prajapati
Cardiovascular Research Institute, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
Chen
C
Liang
Cardiovascular Research Institute, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
Masanari
M
Umemura
Cardiovascular Research Institute, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
Utako
U
Yokoyama
Cardiovascular Research Institute, Yokohama City University Graduate School of Medicine, Yokohama, Japan; Department of Physiology, Aichi Medical University, Aichi, Japan.
Motohiko
M
Sato
Cardiovascular Research Institute, Yokohama City University Graduate School of Medicine, Yokohama, Japan; Tsurumi University School of Dental Medicine, Yokohama, Japan. Electronic address: okumura-s@tsurumi-u.ac.jp.
Satoshi
S
Okumura
Cardiovascular Research Institute, Yokohama City University Graduate School of Medicine, Yokohama, Japan. Electronic address: yishikaw@med.yokohama-cu.ac.jp.
Yoshihiro
Y
Ishikawa
D000262:Adenylyl Cyclases / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis; D001281:Atrial Fibrillation / Q000209:etiology / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D002395:Catecholamines / Q000378:metabolism*; D005355:Fibrosis; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009206:Myocardium / Q000378:metabolism / Q000473:pathology*; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000473:pathology; D013312:Stress, Physiological
D002395:Catecholamines; C482601:Epac protein, mouse; D020662:Guanine Nucleotide Exchange Factors; D000262:Adenylyl Cyclases; C419510:adenylyl cyclase type V
Adenylyl cyclase; Arrhythmia; Catecholamine; Epac; Heart failure