TY - JOUR
T1 - Cardiac myocyte-secreted cAMP exerts paracrine action via adenosine receptor activation
AU - Sassi, Yassine
AU - Ahles, Andrea
AU - Truong, Dong Jiunn Jeffery
AU - Baqi, Younis
AU - Lee, Sang Yong
AU - Husse, Britta
AU - Hulot, Jean Sébastien
AU - Foinquinos, Ariana
AU - Thum, Thomas
AU - Müller, Christa E.
AU - Dendorfer, Andreas
AU - Laggerbauer, Bernhard
AU - Engelhardt, Stefan
N1 - Publisher Copyright:
© 2014, American Society for Clinical Investigation. All rights reserved.
PY - 2014/12/1
Y1 - 2014/12/1
N2 - Acute stimulation of cardiac β-adrenoceptors is crucial to increasing cardiac function under stress; however, sustained β-adrenergic stimulation has been implicated in pathological myocardial remodeling and heart failure. Here, we have demonstrated that export of cAMP from cardiac myocytes is an intrinsic cardioprotective mechanism in response to cardiac stress. We report that infusion of cAMP into mice averted myocardial hypertrophy and fibrosis in a disease model of cardiac pressure overload. The protective effect of exogenous cAMP required adenosine receptor signaling. This observation led to the identification of a potent paracrine mechanism that is dependent on secreted cAMP. Specifically, FRET-based imaging of cAMP formation in primary cells and in myocardial tissue from murine hearts revealed that cardiomyocytes depend on the transporter ABCC4 to export cAMP as an extracellular signal. Extracellular cAMP, through its metabolite adenosine, reduced cardiomyocyte cAMP formation and hypertrophy by activating A1 adenosine receptors while delivering an antifibrotic signal to cardiac fibroblasts by A2 adenosine receptor activation. Together, our data reveal a paracrine role for secreted cAMP in intercellular signaling in the myocardium, and we postulate that secreted cAMP may also constitute an important signal in other tissues.
AB - Acute stimulation of cardiac β-adrenoceptors is crucial to increasing cardiac function under stress; however, sustained β-adrenergic stimulation has been implicated in pathological myocardial remodeling and heart failure. Here, we have demonstrated that export of cAMP from cardiac myocytes is an intrinsic cardioprotective mechanism in response to cardiac stress. We report that infusion of cAMP into mice averted myocardial hypertrophy and fibrosis in a disease model of cardiac pressure overload. The protective effect of exogenous cAMP required adenosine receptor signaling. This observation led to the identification of a potent paracrine mechanism that is dependent on secreted cAMP. Specifically, FRET-based imaging of cAMP formation in primary cells and in myocardial tissue from murine hearts revealed that cardiomyocytes depend on the transporter ABCC4 to export cAMP as an extracellular signal. Extracellular cAMP, through its metabolite adenosine, reduced cardiomyocyte cAMP formation and hypertrophy by activating A1 adenosine receptors while delivering an antifibrotic signal to cardiac fibroblasts by A2 adenosine receptor activation. Together, our data reveal a paracrine role for secreted cAMP in intercellular signaling in the myocardium, and we postulate that secreted cAMP may also constitute an important signal in other tissues.
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U2 - 10.1172/JCI74349
DO - 10.1172/JCI74349
M3 - Article
C2 - 25401477
AN - SCOPUS:84915820638
SN - 0021-9738
VL - 124
SP - 5385
EP - 5397
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
IS - 12
ER -