Osteopontin deletion enhances beta2-adrenergic receptor-dependent anti-fibrotic signaling in cardiomyocytes, suggesting OPN blockade as a potential therapeutic target for cardiac fibrosis.
Cardiac 2-adrenergic receptors (ARs) are known to inhibit collagen production and fibrosis in cardiac fibroblasts and myocytes. The 2AR is a Gs protein-coupled receptor (GPCR) and, upon its activation, stimulates 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, mediating also fibrosis in several tissues, including the heart. OPN underlies several cardiovascular pathologies, including atherosclerosis and cardiac adverse remodeling. We have found that the cardiotoxic hormone aldosterone transcriptionally upregulates OPN in H9c2 rat cardiac myoblasts, an effect prevented by endogenous 2AR activation. Additionally, CRISPR-mediated OPN deletion enhances cAMP generation in response to both b1AR and 2AR activation in H9c2 cardiomyocytes, leading to upregulation of Epac1 protein levels. These effects render 2AR stimulation capable of completely abrogating transforming growth factor (TGF)--dependent fibrosis in OPN-lacking H9c2 cardiomyocytes. Finally, OPN interacts constitutively with Gas subunits in H9c2 cardiac cells. Thus, we have uncovered a direct inhibitory role of OPN in cardiac 2AR anti-fibrotic signaling via cAMP/Epac1. OPN blockade could be of value in the treatment and/or prevention of cardiac fibrosis.
Pollard et al. (2019) studied this question.