Molecular inotropy mediated by cardiac miR-based PDE4D/PRKAR1α/phosphoprotein signaling.

Fikru B Bedada,Joseph M Metzger,Erik Arden,Joshua J Martindale

doi:10.1038/srep36803

Fikru B Bedada, Joseph M Metzger + Show 2 more

Open Access

https://doi.org/10.1038/srep36803

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Journal: Scientific Reports	Publication Date: Nov 11, 2016
Citations: 8	License type: CC BY 4.0

Affiliation: University of Minnesota Medical Center

Abstract

Molecular inotropy refers to cardiac contractility that can be modified to affect overall heart pump performance. Here we show evidence of a new molecular pathway for positive inotropy by a cardiac-restricted microRNA (miR). We report enhanced cardiac myocyte performance by acute titration of cardiac myosin-embedded miR-208a. The observed positive effect was independent of host gene myosin effects with evidence of negative regulation of cAMP-specific 3′,5′-cyclic phosphodiesterase 4D (PDE4D) and the regulatory subunit of PKA (PRKAR1α) content culminating in PKA-site dependent phosphorylation of cardiac troponin I (cTnI) and phospholamban (PLN). Further, acute inhibition of miR-208a in adult myocytes in vitro increased PDE4D expression causing reduced isoproterenol-mediated phosphorylation of cTnI and PLN. Next, rAAV-mediated miR-208a gene delivery enhanced heart contractility and relaxation parameters in vivo. Finally, acute inducible increases in cardiac miR-208a in vivo reduced PDE4D and PRKAR1α, with evidence of increased content of several complementary miRs harboring the PDE4D recognition sequence. Physiologically, this resulted in significant cardiac cTnI and PLN phosphorylation and improved heart performance in vivo. As phosphorylation of cTnI and PLN is critical to myocyte function, titration of miR-208a represents a potential new mechanism to enhance myocardial performance via the PDE4D/PRKAR1α/PKA phosphoprotein signaling pathway.

Highlights

Myocardial performance is tightly linked to the contractile state of the cardiac myocyte[1]
We report evidence of a new signaling mechanism of positive inotropy whereby a cardiac myosin-embedded miR targets suppression of cAMP-specific 3′, 5′-cyclic phosphodiesterase 4D and protein kinase A regulatory subunit I alpha (PRKAR1α)
Findings show that with acute increases in miR-208a, phosphodiesterase 4D (PDE4D) and PRKAR1αprotein content is significantly reduced in cardiac myocytes causing increased PKA site-dependent phosphorylation of troponin I and phospholamban (PLN)

Summary

Introduction

Myocardial performance is tightly linked to the contractile state of the cardiac myocyte[1]. The MYH6 gene embeds the cardiac restricted miR-208a whose expression, like the host gene, can be depressed in chronic heart disease[16,17,23,24] It is unclear, whether cardiac specific miR-208a has a direct or indirect effect on cardiac function independent of host gene myosin effects. We report that miR-208a-mediated decreased PDE4D and PRKAR1αcontent leads to increased PKA-site specific phosphorylation of vital cardiac phosphoproteins troponin I and phospholamban. These cardiac phosphosubstrates are well known modulators of myocyte performance[28,29,30] and are sufficient to account for the observed improved cellular performance. These findings are evidence of a new mechanism for miRs by acutely enhancing myocyte performance via the PDE4D/PRKAR1α/PKA/myofilament signaling pathway

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