Preservation of myocardial fatty acid oxidation prevents diastolic dysfunction in mice subjected to angiotensin II infusion.
BACKGROUND
Diastolic dysfunction is a common feature in many heart failure patients with preserved ejection fraction and has been associated with altered myocardial metabolism in hypertensive and diabetic patients. Therefore, metabolic interventions to improve diastolic function are warranted. In mice with a germline cardiac-specific deletion of acetyl CoA carboxylase 2 (ACC2), systolic dysfunction induced by pressure-overload was prevented by maintaining cardiac fatty acid oxidation (FAO). However, it has not been evaluated whether this strategy would prevent the development of diastolic dysfunction in the adult heart.


OBJECTIVE
To test the hypothesis that augmenting cardiac FAO is protective against angiotensin II (AngII)-induced diastolic dysfunction in an adult mouse heart.


RESULTS
We generated a mouse model to induce cardiac-specific deletion of ACC2 in adult mice. Tamoxifen treatment (20mg/kg/day for 5days) was sufficient to delete ACC2 protein and increase cardiac FAO by 50% in ACC2 flox/flox-MerCreMer+mice (iKO). After 4weeks of AngII (1.1mg/kg/day), delivered by osmotic mini-pumps, iKO mice showed normalized E/E' and E'/A' ratios compared to AngII treated controls (CON). The prevention of diastolic dysfunction in iKO-AngII was accompanied by maintained FAO and reduced glycolysis and anaplerosis. Furthermore, iKO-AngII hearts had a~50% attenuation of cardiac hypertrophy and fibrosis compared to CON. In addition, maintenance of FAO in iKO hearts suppressed AngII-associated increases in oxidative stress and sustained mitochondrial respiratory complex activities.


CONCLUSIONS
These data demonstrate that impaired FAO is a contributor to the development of diastolic dysfunction induced by AngII. Maintenance of FAO in this model leads to an attenuation of hypertrophy, reduces fibrosis, suppresses increases in oxidative stress, and maintains mitochondrial function. Therefore, targeting mitochondrial FAO is a promising therapeutic strategy for the treatment of diastolic dysfunction.
Mitochondria and Metabolism Center, Department of Anesthesiology & Pain Medicine, University of Washington, Seattle, WA, United States.
Yong Seon
YS
Choi
Mitochondria and Metabolism Center, Department of Anesthesiology & Pain Medicine, University of Washington, Seattle, WA, United States.
Ana Barbosa Marcondes
AB
de Mattos
Mitochondria and Metabolism Center, Department of Anesthesiology & Pain Medicine, University of Washington, Seattle, WA, United States.
Dan
D
Shao
Mitochondria and Metabolism Center, Department of Anesthesiology & Pain Medicine, University of Washington, Seattle, WA, United States.
Tao
T
Li
Mitochondria and Metabolism Center, Department of Anesthesiology & Pain Medicine, University of Washington, Seattle, WA, United States.
Miranda
M
Nabben
Mitochondria and Metabolism Center, Department of Anesthesiology & Pain Medicine, University of Washington, Seattle, WA, United States.
Maengjo
M
Kim
Mitochondria and Metabolism Center, Department of Anesthesiology & Pain Medicine, University of Washington, Seattle, WA, United States.
Wang
W
Wang
Mitochondria and Metabolism Center, Department of Anesthesiology & Pain Medicine, University of Washington, Seattle, WA, United States. Electronic address: rongtian@u.washington.edu.
Rong
R
Tian
Mitochondria and Metabolism Center, Department of Anesthesiology & Pain Medicine, University of Washington, Seattle, WA, United States. Electronic address: skolwicz@u.washington.edu.
Stephen C
SC
Kolwicz
D000103:Acetyl-CoA Carboxylase / Q000172:deficiency; D000804:Angiotensin II / Q000008:administration & dosage*; D000818:Animals; D006332:Cardiomegaly / Q000175:diagnosis / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D003971:Diastole / Q000187:drug effects; D004195:Disease Models, Animal; D004452:Echocardiography; D004734:Energy Metabolism / Q000235:genetics; D005227:Fatty Acids / Q000378:metabolism*; D005355:Fibrosis; D017353:Gene Deletion; D008279:Magnetic Resonance Imaging; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology / Q000648:ultrastructure; D001678:Organelle Biogenesis; D010084:Oxidation-Reduction / Q000187:drug effects*; D018384:Oxidative Stress / Q000235:genetics; D018754:Ventricular Dysfunction / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*
D005227:Fatty Acids; D000804:Angiotensin II; C498191:Acacb protein, mouse; D000103:Acetyl-CoA Carboxylase
ACC2; Cardiac metabolism; Hypertrophy; Lipids; Myocardium; [105] Contractile function; [107] Biochemistry and metabolism; [140] energy metabolism; [145] genetically altered mice; [90] Lipid and lipoprotein metabolism
Arch Biochem Biophys. 2002 Oct 15;406(2):222-8
12361710
JAMA. 2011 Aug 24;306(8):856-63
21862747
Nat Protoc. 2012 May 31;7(6):1235-46
22653162
Cardiovasc Res. 2005 Jun 1;66(3):454-61
15914110
Circulation. 2016 Feb 23;133(8):698-705
26819376
Circ Heart Fail. 2014 Jan;7(1):104-15
24249049
Physiol Genomics. 2004 Jul 08;18(2):152-66
15126644
Am J Physiol Heart Circ Physiol. 2013 Apr 15;304(8):H1103-13
23396452
J Vis Exp. 2010 Aug 31;(42):null
20834220
Circ Res. 2011 Apr 1;108(7):837-46
21311045
Circ Heart Fail. 2013 Sep 1;6(5):944-52
23811963
Adv Nutr. 2013 Mar 01;4(2):157-63
23493532
Circ Res. 2001 May 11;88(9):961-8
11349007
Antioxid Redox Signal. 2013 Oct 1;19(10):1085-94
22443458
Circ Res. 2000 Mar 17;86(5):580-8
10720420
Physiol Rev. 2010 Jan;90(1):207-58
20086077
Circulation. 2012 Oct 2;126(14):1705-16
22932257
Circulation. 1996 Dec 1;94(11):2837-42
8941110
Am J Physiol Heart Circ Physiol. 2009 Mar;296(3):H550-8
19151249
Am J Physiol. 1994 Aug;267(2 Pt 2):H742-50
8067430
Circulation. 2016 Feb 23;133(8):706-16
26819374
Hypertension. 2000 Jun;35(6):1183-8
10856260
Cardiovasc Res. 2001 Oct;52(1):103-10
11557238
Circulation. 2012 Jun 12;125(23 ):2844-53
22586279
Circulation. 2011 May 10;123(18):2006-13; discussion 2014
21555723
Diabetes. 2015 Aug;64(8):2817-27
25858561
J Cardiovasc Pharmacol. 2008 Jan;51(1):62-70
18209570
J Mol Cell Cardiol. 2013 Oct;63:98-106
23886814
Curr Cardiol Rep. 2014 Jul;16(7):501
24893938
Int J Obes Relat Metab Disord. 2001 Mar;25(3):378-88
11319636
Int J Cardiol. 2013 Mar 10;163(3):320-5
23073279
Cardiovasc Res. 2000 Mar;45(4):860-5
10728411
Circ Res. 2012 Aug 31;111(6):728-38
22730442
Nat Rev Cardiol. 2011 Jan;8(1):30-41
21060326
Circ Heart Fail. 2009 Mar;2(2):105-12
19808325
Circulation. 2011 Dec 6;124(23 ):2491-501
22064591
Proc Natl Acad Sci U S A. 1997 Oct 14;94(21):11168-72
9326580
Mol Cell Biochem. 2008 Apr;311(1-2):215-24
18278440
J Clin Invest. 2012 Nov;122(11):3919-30
23023704
Am J Physiol Heart Circ Physiol. 2013 Aug 1;305(3):H397-402
23709599
J Clin Invest. 2001 Apr;107(7):813-22
11285300
Prog Cardiovasc Dis. 2005 Mar-Apr;47(5):320-32
16003647
Diabetes. 2007 Oct;56(10):2457-66
17623815
Circulation. 1999 May 4;99(17):2261-7
10226091
J Biol Chem. 2001 Nov 30;276(48):44390-5
11574533
Circ Heart Fail. 2012 Jul 1;5(4):493-503
22705769
Circulation. 1997 Aug 19;96(4):1313-9
9286964
Aging (Albany NY). 2016 Feb;8(2):314-27
26872208
Biochim Biophys Acta. 2010 Jun-Jul;1797(6-7):929-38
20085746