Cardiac myocyte–secreted cAMP exerts paracrine action via adenosine receptor activation
Yassine Sassi, … , Bernhard Laggerbauer, Stefan Engelhardt
Yassine Sassi, … , Bernhard Laggerbauer, Stefan Engelhardt
Published November 17, 2014
Citation Information: J Clin Invest. 2014;124(12):5385-5397. https://doi.org/10.1172/JCI74349.
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Research Article Cardiology

Cardiac myocyte–secreted cAMP exerts paracrine action via adenosine receptor activation

Abstract

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.

Authors

Yassine Sassi, Andrea Ahles, Dong-Jiunn Jeffery Truong, Younis Baqi, Sang-Yong Lee, Britta Husse, Jean-Sébastien Hulot, Ariana Foinquinos, Thomas Thum, Christa E. Müller, Andreas Dendorfer, Bernhard Laggerbauer, Stefan Engelhardt

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Figure 2

Exogenous cAMP confers opposing changes of intracellular cAMP in CMs and CFs.

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Exogenous cAMP confers opposing changes of intracellular cAMP in CMs and...
(A) Quantification of endogenous adenosine receptor subtype expression in NRCMs (by qPCR, n = 3). (B) Real-time measurement of intracellular (intrac.) cAMP formation (shown as CFP/YFP ratio) in NRCMs transduced with a FRET-based sensor for cAMP. Cells were stimulated with Iso and cAMP in the absence (top row) or presence (bottom row) of the A1R antagonist DPCPX (100 nM). Scale bar: 10 μm. (C) Intracellular cAMP formation in NRCMs in the presence of Iso, with further addition of cAMP to the medium (100 μM, black), and in the absence or presence of antagonists against A1R (100 nM DPCPX, yellow), A2AR (100 nM SCH-442416, green), A2BR (500 nM PSB-1115, green), A3R (100 nM VUF-5574, blue), and the nonspecific adenosine receptor antagonist DPSPX (10 nM, red). Representative tracings for the different treatment groups. (D) Quantitative analysis of the results. (E) Quantification of endogenous adenosine receptor subtype expression in isolated NRCF (by qPCR, n = 4, 2 days of culture). (F–H) Data derived from NRCF in an order analogous to that in the series above. In NRCF, exogenously added cAMP promoted the formation of intracellular cAMP (F and G). Scale bar: 10 μm. Inhibition of A2AR or of A2BR (green tracings/bar) prevented the intracellular response to extracellular cAMP. (H) Quantitative FRET data were obtained from at least 9 cells/group. *P < 0.05; **P < 0.01; ***P < 0.001.