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 4

Intercellular communication through secreted cAMP between CMs and CFs in cocultures and living cardiac tissue.

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Intercellular communication through secreted cAMP between CMs and CFs in...
(A) Experimental scheme to assess the role of secreted cAMP in cocultures of CMs and CFs. Primary CFs from Adrb1–/– Adrb2–/– mice (green) were infected with an adenovirus for the expression of a FRET-cAMP sensor (termed sensor CFs). WT NRCMs (yellow) were plated on top of the cultured primary CFs. The response of CFs to CM-derived cAMP (after stimulation with 10 μM Iso) was monitored by FRET. (B) Representative FRET recordings in CFs after Iso-induced cAMP export from CMs. PBS served as a negative control. (C) Quantification of the results. n = 10–15 cells (3–6 independent experiments). **P < 0.01, determined by unpaired t test with Welch’s correction. (D) Multicolor 2-photon images of a slice from cultured mouse myocardium to which sensor CFs had been transplanted. Histochemical stainings were for phalloidin (red), adenovirus-encoded cAMP-sensor (YFP, green), and propidium iodide (PI, blue). Image perspectives are overhead (large), horizontal (top), and vertical (right) cross sections. Arrowheads indicate the addition of isoproterenol or PBS. Scale bar: 20 μm. (E) cAMP formation in individual CFs after incubation of WT myocardial slices with Iso (black circles) or PBS (white circles, black outline). Data from an analogous experiment with slices from Abcc4–/– mice are displayed in red (red circles, Iso; white circles, red outline, PBS). (F) Quantification of the results. n = 7–15 cells from 3–5 independent experiments. ***P <0.001, NS, not significant versus WT; Iso determined by 2-way ANOVA with Bonferroni’s post hoc analysis.