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Open AccessArticle

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

1
Laboratory for the Study of Neurohormonal Control of the Circulation, Department of Pharmaceutical Sciences (Pharmacology), College of Pharmacy; Nova Southeastern University, Fort Lauderdale, FL 33328, USA
2
Department of Medicine, University of Miami Miller School of Medicine, Miami, FL 33136, USA
*
Author to whom correspondence should be addressed.
Present address: Jackson Memorial Hospital, Miami, FL 33136, USA.
Present address: Massachusetts General Hospital, Boston, MA 02114, USA.
§
American Foundation for Pharmaceutical Education (AFPE) “Gateway to Research” Scholar.
Int. J. Mol. Sci. 2019, 20(6), 1396; https://doi.org/10.3390/ijms20061396
Received: 28 February 2019 / Revised: 13 March 2019 / Accepted: 15 March 2019 / Published: 20 March 2019
(This article belongs to the Special Issue Mechanisms of Inflammation in Degenerative Cardiovascular Conditions)
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-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 β2AR activation. Additionally, CRISPR-mediated OPN deletion enhanced cAMP generation in response to both β1AR and β2AR activation in H9c2 cardiomyocytes, leading to the upregulation of Epac1 protein levels. These effects rendered β2AR stimulation capable of completely abrogating transforming growth factor (TGF)-β-dependent fibrosis in OPN-lacking H9c2 cardiomyocytes. Finally, OPN interacted constitutively with Gαs subunits in H9c2 cardiac cells. Thus, we uncovered a direct inhibitory role of OPN in cardiac β2AR anti-fibrotic signaling via cAMP/Epac1. OPN blockade could be of value in the treatment and/or prevention of cardiac fibrosis. View Full-Text
Keywords: β2-adrenergic receptor; cAMP; cardiac myocytes; CRISPR; Epac1; fibrosis; osteopontin; signal transduction β2-adrenergic receptor; cAMP; cardiac myocytes; CRISPR; Epac1; fibrosis; osteopontin; signal transduction
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Pollard, C.M.; Desimine, V.L.; Wertz, S.L.; Perez, A.; Parker, B.M.; Maning, J.; McCrink, K.A.; Shehadeh, L.A.; Lymperopoulos, A. Deletion of Osteopontin Enhances β2-Adrenergic Receptor-Dependent Anti-Fibrotic Signaling in Cardiomyocytes. Int. J. Mol. Sci. 2019, 20, 1396.

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