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Deletion of Osteopontin Enhances ??-Adrenergic Receptor-Dependent Anti-Fibrotic Signaling in Cardiomyocytes.


ABSTRACT: Cardiac ??-adrenergic receptors (ARs) are known to inhibit collagen production and fibrosis in cardiac fibroblasts and myocytes. The ??AR is a Gs protein-coupled receptor (GPCR) and, upon its activation, stimulates the generation of cyclic 3',5'-adenosine monophosphate (cAMP). cAMP has two effectors: protein kinase A (PKA) and the exchange protein directly activated by cAMP (Epac). Epac1 has been shown to inhibit cardiac fibroblast activation and fibrosis. Osteopontin (OPN) is a ubiquitous pro-inflammatory cytokine, which also mediates fibrosis in several tissues, including the heart. OPN underlies several cardiovascular pathologies, including atherosclerosis and cardiac adverse remodeling. We found that the cardiotoxic hormone aldosterone transcriptionally upregulates OPN in H9c2 rat cardiac myoblasts-an effect prevented by endogenous ??AR activation. Additionally, CRISPR-mediated OPN deletion enhanced cAMP generation in response to both ??AR and ??AR activation in H9c2 cardiomyocytes, leading to the upregulation of Epac1 protein levels. These effects rendered ??AR stimulation capable of completely abrogating transforming growth factor (TGF)-?-dependent fibrosis in OPN-lacking H9c2 cardiomyocytes. Finally, OPN interacted constitutively with G?s subunits in H9c2 cardiac cells. Thus, we uncovered a direct inhibitory role of OPN in cardiac ??AR anti-fibrotic signaling via cAMP/Epac1. OPN blockade could be of value in the treatment and/or prevention of cardiac fibrosis.

SUBMITTER: Pollard CM 

PROVIDER: S-EPMC6470638 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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Deletion of Osteopontin Enhances β₂-Adrenergic Receptor-Dependent Anti-Fibrotic Signaling in Cardiomyocytes.

Pollard Celina M CM   Desimine Victoria L VL   Wertz Shelby L SL   Perez Arianna A   Parker Barbara M BM   Maning Jennifer J   McCrink Katie A KA   Shehadeh Lina A LA   Lymperopoulos Anastasios A  

International journal of molecular sciences 20190320 6


Cardiac β₂-adrenergic receptors (ARs) are known to inhibit collagen production and fibrosis in cardiac fibroblasts and myocytes. The β₂AR is a Gs protein-coupled receptor (GPCR) and, upon its activation, stimulates the generation of cyclic 3',5'-adenosine monophosphate (cAMP). cAMP has two effectors: protein kinase A (PKA) and the exchange protein directly activated by cAMP (Epac). Epac1 has been shown to inhibit cardiac fibroblast activation and fibrosis. Osteopontin (OPN) is a ubiquitous pro-i  ...[more]

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