Molecular inotropy mediated by cardiac miR-based PDE4D/PRKAR1α/phosphoprotein signaling.
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.
Department of Integrative Biology and Physiology, University of Minnesota Medical School, 6-125 Jackson Hall, 321 Church Street SE, Minneapolis, MN 55455 USA.
Fikru B
FB
Bedada
Department of Integrative Biology and Physiology, University of Minnesota Medical School, 6-125 Jackson Hall, 321 Church Street SE, Minneapolis, MN 55455 USA.
Joshua J
JJ
Martindale
Department of Integrative Biology and Physiology, University of Minnesota Medical School, 6-125 Jackson Hall, 321 Church Street SE, Minneapolis, MN 55455 USA.
Erik
E
Arden
Department of Integrative Biology and Physiology, University of Minnesota Medical School, 6-125 Jackson Hall, 321 Church Street SE, Minneapolis, MN 55455 USA.
Joseph M
JM
Metzger
D020413:3' Untranslated Regions; D000818:Animals; D001483:Base Sequence; D001665:Binding Sites; D002135:Calcium-Binding Proteins / Q000378:metabolism; D002478:Cells, Cultured; D054756:Cyclic AMP-Dependent Protein Kinase RIalpha Subunit / Q000378:metabolism*; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4 / Q000235:genetics / Q000378:metabolism*; D015870:Gene Expression; D006352:Heart Ventricles / Q000166:cytology; D051379:Mice; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D009200:Myocardial Contraction; D032383:Myocytes, Cardiac / Q000502:physiology; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D034622:RNA Interference; D051381:Rats; D015398:Signal Transduction; D019210:Troponin I / Q000378:metabolism; D000099211:Phospholamban
D020413:3' Untranslated Regions; D002135:Calcium-Binding Proteins; D054756:Cyclic AMP-Dependent Protein Kinase RIalpha Subunit; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D035683:MicroRNAs; D010750:Phosphoproteins; D019210:Troponin I; D000099211:Phospholamban; C543978:Mirn208 microRNA, mouse; C517836:Prkar1a protein, rat; C528468:PDE4D protein, rat