Posttranslational modulation of FoxO1 contributes to cardiac remodeling in post-ischemic heart failure.
Forkhead box protein O1 (FoxO1) plays a key role in energy homeostasis, stress response and autophagy and is dysregulated in diabetes and ischemia. We investigated cardiac FoxO1 expression and posttranstranslational modifications after myocardial infarction (MI) and further tested if active posttranstranslational modulation of FoxO1 can alter cardiac remodeling in postischemic heart failure.



Non-diabetic and diabetic C57BL/6 mice were subjected to MI by ligation of left anterior descending artery. In selected experiments we combined this model with intramyocardial injection of adenovirus expressing different isoforms of FoxO1. We used Millar catheter, histology, Western blot and metabolomics for further analyses.



We show that after MI total cardiac FoxO1 is downregulated and partly recovers after 7 days. This downregulation is accompanied by fundamental posttranslational modifications of FoxO1, particularly acetylation. Adenovirus experiments revealed smaller infarction size and improved heart function in mice expressing a constitutively deacetylated variant of FoxO1 compared to a wild type variant of FoxO1 in both non-diabetic (MI size: -13.4 ± 3.5%; LVDP: +29.1 ± 9.4  mmHg; p < 0.05) and diabetic mice (MI size: -17.6 ± 3.7%; LVDP: +10.9 ± 3.6  mmHg; p < 0.05). Metabolomics analyses showed alterations in metabolites connected to muscle breakdown, collagen/elastin and energy metabolism between the two groups.



First, our results demonstrate that myocardial ischemia is associated with downregulation and posttranslational modification of cardiac FoxO1. Second, we show in a mouse model of postischemic heart failure that posttranslational modulation of FoxO1 alters heart function involving collagen and protein metabolism. Therefore, posttranslational modifications of FoxO1 could be an option to target remodeling processes in postischemic heart failure.
Department of Systems Medicine, University of Rome Tor Vergata, 00133 Rome, Italy; Department of Internal Medicine I, University Hospital Aachen, Pauwelsstraße 30, 52074 Aachen, Germany.
Ben Arpad
BA
Kappel
Department of Systems Medicine, University of Rome Tor Vergata, 00133 Rome, Italy; Department of Internal Medicine I, University Hospital Aachen, Pauwelsstraße 30, 52074 Aachen, Germany.
Robert
R
Stöhr
Department of Systems Medicine, University of Rome Tor Vergata, 00133 Rome, Italy.
Lorenzo
L
De Angelis
Department of Systems Medicine, University of Rome Tor Vergata, 00133 Rome, Italy.
Maria
M
Mavilio
Department of Systems Medicine, University of Rome Tor Vergata, 00133 Rome, Italy.
Rossella
R
Menghini
Department of Systems Medicine, University of Rome Tor Vergata, 00133 Rome, Italy; Center for Atherosclerosis, Department of Medicine, Policlinico Tor Vergata, 00133 Rome, Italy. Electronic address: federicm@uniroma2.it.
Massimo
M
Federici
D000107:Acetylation; D000818:Animals; D003094:Collagen / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000097:blood / Q000235:genetics; D015536:Down-Regulation; D004734:Energy Metabolism; D000071161:Forkhead Box Protein O1 / Q000235:genetics / Q000502:physiology*; D005786:Gene Expression Regulation; D006333:Heart Failure / Q000378:metabolism / Q000473:pathology*; D006439:Hemodynamics; D008297:Male; D055432:Metabolomics; D051379:Mice; D008810:Mice, Inbred C57BL; D009203:Myocardial Infarction / Q000378:metabolism / Q000473:pathology; D017202:Myocardial Ischemia / Q000473:pathology*; D018384:Oxidative Stress; D011499:Protein Processing, Post-Translational; D020257:Ventricular Remodeling
D000071161:Forkhead Box Protein O1; C467200:Foxo1 protein, mouse; D003094:Collagen
Acetylation; Cardiac remodeling; Diabetes; FoxO1; Heart failure; Myocardial infarction; Posttranslational modification