title: Epac activation inhibits IL-6-induced cardiac myocyte dysfunction.
abstract: Pro-inflammatory cytokines are released in septic shock and impair cardiac function via the Jak-STAT pathway. It is well known that sympathetic and thus catecholamine signaling is activated thereafter to compensate for cardiac dysfunction. The mechanism of such compensation by catecholamine signaling has been traditionally understood to be cyclic AMP-dependent protein kinase (PKA)-mediated enforcement of cardiac contractility. We hypothesized that the exchange protein activated by cAMP (Epac), a newly identified target of cAMP signaling that functions independently of PKA, also plays a key role in this mechanism. In cultured cardiac myocytes, activation of Epac attenuated the inhibitory effect of interleukin-6 on the increase of intracellular Ca2+concentration and contractility in response to isoproterenol, most likely through inhibition of the Jak-STAT pathway via SOCS3, with subsequent changes in inducible nitric oxide synthase expression. These findings suggest a new role of catecholamine signaling in compensating for cardiac dysfunction in heart failure. Epac and its downstream pathway may be a novel target for treating cardiac dysfunction in endotoxemia.
authors.affiliation: Cardiovascular Research Institute, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama, 236-0004, Japan.
authors.forename: Huiling
authors.initials: H
authors.lastname: Jin
authors.affiliation: Cardiovascular Research Institute, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama, 236-0004, Japan.
authors.forename: Takayuki
authors.initials: T
authors.lastname: Fujita
authors.affiliation: Cardiovascular Research Institute, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama, 236-0004, Japan.|Department of Cardiac Physiology, National Cerebral and Cardiovascular Center Research Institute, 5-7-1 Fujishirodai, Suita-shi, Osaka, 565-8565, Japan.
authors.forename: Meihua
authors.initials: M
authors.lastname: Jin
authors.affiliation: Cardiovascular Research Institute, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama, 236-0004, Japan.|Biochemical Engineering, Faculty of Engineering, Yamagata University, 4-3-16, Jonan, Yonezawa, Yamagata, 992-8510, Japan.
authors.forename: Reiko
authors.initials: R
authors.lastname: Kurotani
authors.affiliation: Cardiovascular Research Institute, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama, 236-0004, Japan.
authors.forename: Yuko
authors.initials: Y
authors.lastname: Hidaka
authors.affiliation: Cardiovascular Research Institute, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama, 236-0004, Japan.
authors.forename: Wenqian
authors.initials: W
authors.lastname: Cai
authors.affiliation: Cardiovascular Research Institute, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama, 236-0004, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Suita
authors.affiliation: Cardiovascular Research Institute, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama, 236-0004, Japan.
authors.forename: Rajesh
authors.initials: R
authors.lastname: Prajapati
authors.affiliation: Cardiovascular Research Institute, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama, 236-0004, Japan.
authors.forename: Chen
authors.initials: C
authors.lastname: Liang
authors.affiliation: Department of Physiology, Tsurumi University School of Dental Medicine, 2-1-3 Tsurumi, Tsurumi-ku, Yokohama, 230-8501, Japan.
authors.forename: Yoshiki
authors.initials: Y
authors.lastname: Ohnuki
authors.affiliation: Department of Physiology, Tsurumi University School of Dental Medicine, 2-1-3 Tsurumi, Tsurumi-ku, Yokohama, 230-8501, Japan.
authors.forename: Yasumasa
authors.initials: Y
authors.lastname: Mototani
authors.affiliation: Cardiovascular Research Institute, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama, 236-0004, Japan.
authors.forename: Masanari
authors.initials: M
authors.lastname: Umemura
authors.affiliation: Cardiovascular Research Institute, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama, 236-0004, Japan.
authors.forename: Utako
authors.initials: U
authors.lastname: Yokoyama
authors.affiliation: Cardiovascular Research Institute, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama, 236-0004, Japan.|Department of Physiology, Aichi Medical University, 1-1 Yazakokarimata, Nagakute, Aichi, 480-1195, Japan.
authors.forename: Motohiko
authors.initials: M
authors.lastname: Sato
authors.affiliation: Cardiovascular Research Institute, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama, 236-0004, Japan. okumura-s@tsurumi-u.ac.jp.|Department of Physiology, Tsurumi University School of Dental Medicine, 2-1-3 Tsurumi, Tsurumi-ku, Yokohama, 230-8501, Japan. okumura-s@tsurumi-u.ac.jp.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Okumura
authors.affiliation: Cardiovascular Research Institute, Yokohama City University Graduate School of Medicine, 3-9 Fukuura, Kanazawa-ku, Yokohama, 236-0004, Japan. yishikaw@yokohama-cu.ac.jp.
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Ishikawa
mesh_terms: D000818:Animals; D000242:Cyclic AMP / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D020662:Guanine Nucleotide Exchange Factors / Q000378:metabolism*; D006333:Heart Failure / Q000378:metabolism* / Q000503:physiopathology*; D015850:Interleukin-6 / Q000378:metabolism*; D053612:Janus Kinases / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D010766:Phosphorylation / Q000502:physiology; D051381:Rats; D050791:STAT Transcription Factors / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D000071223:Suppressor of Cytokine Signaling 3 Protein / Q000378:metabolism
chemical_list: D020662:Guanine Nucleotide Exchange Factors; D015850:Interleukin-6; C526973:Rapgef3 protein, rat; D050791:STAT Transcription Factors; D000071223:Suppressor of Cytokine Signaling 3 Protein; D000242:Cyclic AMP; D052247:Nitric Oxide Synthase Type II; D053612:Janus Kinases; D017868:Cyclic AMP-Dependent Protein Kinases
keywords: Catecholamine; Contractility; Cytokine; Epac; Jak-STAT; cAMP