title: PHD2/3-dependent hydroxylation tunes cardiac response to β-adrenergic stress via phospholamban.
abstract: Ischemic heart disease is the leading cause of heart failure. Both clinical trials and experimental animal studies demonstrate that chronic hypoxia can induce contractile dysfunction even before substantial ventricular damage, implicating a direct role of oxygen in the regulation of cardiac contractile function. Prolyl hydroxylase domain (PHD) proteins are well recognized as oxygen sensors and mediate a wide variety of cellular events by hydroxylating a growing list of protein substrates. Both PHD2 and PHD3 are highly expressed in the heart, yet their functional roles in modulating contractile function remain incompletely understood. Here, we report that combined deletion of Phd2 and Phd3 dramatically decreased expression of phospholamban (PLN), resulted in sustained activation of calcium/calmodulin-activated kinase II (CaMKII), and sensitized mice to chronic β-adrenergic stress-induced myocardial injury. We have provided evidence that thyroid hormone receptor-α (TR-α), a transcriptional regulator of PLN, interacts with PHD2 and PHD3 and is hydroxylated at 2 proline residues. Inhibition of PHDs increased the interaction between TR-α and nuclear receptor corepressor 2 (NCOR2) and suppressed Pln transcription. Together, these observations provide mechanistic insight into how oxygen directly modulates cardiac contractility and suggest that cardiac function could be modulated therapeutically by tuning PHD enzymatic activity.
authors.forename: Liang
authors.initials: L
authors.lastname: Xie
authors.forename: Xinchun
authors.initials: X
authors.lastname: Pi
authors.forename: W H Davin
authors.initials: WH
authors.lastname: Townley-Tilson
authors.forename: Na
authors.initials: N
authors.lastname: Li
authors.forename: Xander H T
authors.initials: XH
authors.lastname: Wehrens
authors.forename: Mark L
authors.initials: ML
authors.lastname: Entman
authors.forename: George E
authors.initials: GE
authors.lastname: Taffet
authors.forename: Ashutosh
authors.initials: A
authors.lastname: Mishra
authors.forename: Junmin
authors.initials: J
authors.lastname: Peng
authors.forename: Jonathan C
authors.initials: JC
authors.lastname: Schisler
authors.forename: Gerhard
authors.initials: G
authors.lastname: Meissner
authors.forename: Cam
authors.initials: C
authors.lastname: Patterson
mesh_terms: D000818:Animals; D020013:Calcium Signaling; D002135:Calcium-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2 / Q000378:metabolism; D002478:Cells, Cultured; D005260:Female; D006801:Humans; D006900:Hydroxylation; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009200:Myocardial Contraction / Q000502:physiology; D017202:Myocardial Ischemia / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D009206:Myocardium / Q000378:metabolism*; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000473:pathology; D056985:Nuclear Receptor Co-Repressor 2 / Q000378:metabolism; D011393:Procollagen-Proline Dioxygenase / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D011943:Receptors, Adrenergic, beta / Q000378:metabolism*; D013312:Stress, Physiological; D037021:Thyroid Hormone Receptors alpha / Q000378:metabolism; D000099211:Phospholamban
chemical_list: D002135:Calcium-Binding Proteins; D054732:Calcium-Calmodulin-Dependent Protein Kinase Type 2; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases; D056985:Nuclear Receptor Co-Repressor 2; D011393:Procollagen-Proline Dioxygenase; D011943:Receptors, Adrenergic, beta; D037021:Thyroid Hormone Receptors alpha; D000099211:Phospholamban; C497443:Hif1a protein, mouse; C539131:Ncor2 protein, mouse; C522722:PHD3 protein, mouse; C490189:Egln1 protein, mouse