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

Abstract

International audienceAcute 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

Proteostasis in cardiac health and disease

“…Myofibroblasts and immune cells initiate the synthesis of various additional paracrine factors, including growth factors and cytokines. However, paracrine pathways limiting hypertrophy and fibrosis, such as cAMP secre tion, can also be activated by stressed cardiomyocytes 142 . In addition to paracrine routes and remodelling of extra cellular matrix, fibroblasts also communicate with cardio myocytes by direct cell to cell communication, such as via connexins.…”

Cardiac Nonmyocytes in the Hub of Cardiac Hypertrophy

“…79 A recent study demonstrated that, after β-adrenergic stimulation with isoproterenol, cAMP in cardiomyocytes was exported to outside of cells through the ATP-binding cassette transporter and worked as an extracellular signal. 80 Extracellular cAMP, via its metabolite adenosine, acts on cardiomyocytes through A 1 adenosine receptors to inhibit cardiomyocyte hypertrophy, whereas acting on cardiac fibroblasts through A 2 adenosine receptors to suppress cell proliferation and ECM deposition. 80 These findings indicate that cAMP serves as an extracellular autocrine and paracrine molecule, as well as intracellular signaling molecule, to regulate cardiac hypertrophy.…”

“…80 Extracellular cAMP, via its metabolite adenosine, acts on cardiomyocytes through A 1 adenosine receptors to inhibit cardiomyocyte hypertrophy, whereas acting on cardiac fibroblasts through A 2 adenosine receptors to suppress cell proliferation and ECM deposition. 80 These findings indicate that cAMP serves as an extracellular autocrine and paracrine molecule, as well as intracellular signaling molecule, to regulate cardiac hypertrophy.…”

Recent progress in the field of cIMP research

“…cIMP may either be taken up into cells via transporters and exert intracellular effects or may act extracellularly, e.g., by metabolism to inosine and subsequent activation of adenosine receptors (Chen et al, 2014;Seifert et al, 2015;Sassi et al, 2014;Detremmerie et al, 2016). Intracellular effects of cIMP are probably transient because several phosphodiesterases effectively hydrolyze cIMP (Monzel et al, 2014).…”

“…Thus, numerous species beyond rat, mouse, rat, and human should be studied. Such studies should not only include membranepermeable cNMP-acetoxymethyl esters as pharmacological tools but also the native cNMPs that can exert biological effects themselves or via degradation products (Chen et al, 2014;Sassi et al, 2014;Seifert et al, 2015;Detremmerie et al, 2016). Furthermore, the precise molecular mechanism underlying the cIMP-increasing effects of the natural compound thymoquinone must be elucidated.…”