title: Regulation of acetylation restores proteolytic function of diseased myocardium in mouse and human.
abstract: Proteasome complexes play essential roles in maintaining cellular protein homeostasis and serve fundamental roles in cardiac function under normal and pathological conditions. A functional detriment in proteasomal activities has been recognized as a major contributor to the progression of cardiovascular diseases. Therefore, approaches to restore proteolytic function within the setting of the diseased myocardium would be of great clinical significance. In this study, we discovered that the cardiac proteasomal activity could be regulated by acetylation. Histone deacetylase (HDAC) inhibitors (suberoylanilide hydroxamic acid and sodium valproate) enhanced the acetylation of 20S proteasome subunits in the myocardium and led to an elevation of proteolytic capacity. This regulatory paradigm was present in both healthy and acutely ischemia/reperfusion (I/R) injured murine hearts, and HDAC inhibition in vitro restored proteolytic capacities to baseline sham levels in injured hearts. This mechanism of regulation was also viable in failing human myocardium. With 20S proteasomal complexes purified from murine myocardium treated with HDAC inhibitors in vivo, we confirmed that acetylation of 20S subunits directly, at least in part, presents a molecular explanation for the improvement in function. Furthermore, using high-resolution LC-MS/MS, we unraveled the first cardiac 20S acetylome, which identified the acetylation of nine N-termini and seven internal lysine residues. Acetylation on four lysine residues and four N-termini on cardiac proteasomes were novel discoveries of this study. In addition, the acetylation of five lysine residues was inducible via HDAC inhibition, which correlated with the enhancement of 20S proteasomal activity. Taken as a whole, our investigation unveiled a novel mechanism of proteasomal function regulation in vivo and established a new strategy for the potential rescue of compromised proteolytic function in the failing heart using HDAC inhibitors.
authors.affiliation: Department of Physiology, UCLA School of Medicine, Los Angeles, California 90095;
authors.forename: Ding
authors.initials: D
authors.lastname: Wang
authors.forename: Caiyun
authors.initials: C
authors.lastname: Fang
authors.forename: Nobel C
authors.initials: NC
authors.lastname: Zong
authors.forename: David A
authors.initials: DA
authors.lastname: Liem
authors.forename: Martin
authors.initials: M
authors.lastname: Cadeiras
authors.forename: Sarah B
authors.initials: SB
authors.lastname: Scruggs
authors.forename: Hongxiu
authors.initials: H
authors.lastname: Yu
authors.forename: Allen K
authors.initials: AK
authors.lastname: Kim
authors.forename: Pengyuan
authors.initials: P
authors.lastname: Yang
authors.forename: Mario
authors.initials: M
authors.lastname: Deng
authors.forename: Haojie
authors.initials: H
authors.lastname: Lu
authors.forename: Peipei
authors.initials: P
authors.lastname: Ping
mesh_terms: D000107:Acetylation / Q000187:drug effects; D000818:Animals; D002853:Chromatography, Liquid; D005786:Gene Expression Regulation; D006333:Heart Failure / Q000473:pathology / Q000601:surgery; D016027:Heart Transplantation; D006352:Heart Ventricles / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006655:Histone Deacetylases / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology*; D008239:Lysine / Q000378:metabolism; D008297:Male; D051379:Mice; D015428:Myocardial Reperfusion Injury / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D009206:Myocardium / Q000201:enzymology* / Q000473:pathology; D046988:Proteasome Endopeptidase Complex / Q000187:drug effects / Q000235:genetics / Q000302:isolation & purification / Q000378:metabolism; D059748:Proteolysis / Q000187:drug effects; D015398:Signal Transduction; D053719:Tandem Mass Spectrometry; D014635:Valproic Acid / Q000494:pharmacology*; D000077337:Vorinostat
chemical_list: D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D000077337:Vorinostat; D014635:Valproic Acid; D046988:Proteasome Endopeptidase Complex; D006655:Histone Deacetylases; D008239:Lysine
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