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 1

Extracellular cAMP prevents cardiac hypertrophy and fibrosis.

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Extracellular cAMP prevents cardiac hypertrophy and fibrosis. (A–C) Mice...
(A–C) Mice were chronically infused with Iso/PE (30 mg/kg/d each) and, where denoted, with exogenous cAMP (30 mg/kg/d), an A1R antagonist (PSB-16P, 5 mg/kg/d), or an A2AR antagonist (MSX-3, 5 mg/kg/d). After 7 days, mice were sacrificed to assess cardiac remodeling. (A) Representative myocardial tissue sections after staining with Sirius Red (for collagen) and Fast Green counterstaining. Images at higher magnification are shown below. Scale bars: 2 mm (top row); 200 μm (bottom row). (B) Ratio of heart weight–to-tibia length (HW/TL) and (C) quantification of myocardial fibrosis. n = 9–16 mice/group. (D) qPCR analysis of β-myosin heavy chain (Myh7) mRNA in myocardial tissue from the indicated groups. n = 5–9 mice/group. (E) Representative WGA staining of left ventricle tissue after the indicated treatments and (F) quantitative analysis (n = 6–8 mice/group). Scale bar: 50 μm. (G and H) NRCMs were treated with Iso/PE, and where denoted, cAMP (100 μM) was added in the presence or absence of antagonists against A1R (DPCPX; 100 nM), A2AR (SCH-442416; 100 nM), A2BR (PSB-1115; 500 nM), or A3R (VUF-5574; 100 nM). (G) Processed images after immunofluorescent staining of primary CMs by an α-actinin antibody (green cells). Nonmyocyte cells (marked in red) were defined as such if they yielded a DAPI signal, but not a signal for α-actinin. Scale bar: 100 μm. (H) Quantitative analysis of the data (n = 3 experiments in triplicate). *P < 0.05; **P < 0.01; ***P < 0.001.