Cardiomyocyte Krüppel-Like Factor 5 Promotes De Novo Ceramide Biosynthesis and Contributes to Eccentric Remodeling in Ischemic Cardiomyopathy.

Animals Cardiomyopathies / physiopathology Ceramides / metabolism Disease Models, Animal Humans Kruppel-Like Transcription Factors / metabolism Male Mice Myocytes, Cardiac / metabolism Ventricular Remodeling / physiology
cardiomyopathies ceramides heart failure myocardial ischemia

Journal

Circulation
ISSN: 1524-4539
Titre abrégé: Circulation
Pays: United States
ID NLM: 0147763

Informations de publication

Date de publication:
16 03 2021
Historique:
pubmed: 13 1 2021
medline: 24 12 2021
entrez: 12 1 2021
Statut: ppublish

Résumé

We previously showed that cardiomyocyte Krϋppel-like factor (KLF) 5 regulates cardiac fatty acid oxidation. As heart failure has been associated with altered fatty acid oxidation, we investigated the role of cardiomyocyte KLF5 in lipid metabolism and pathophysiology of ischemic heart failure. Using real-time polymerase chain reaction and Western blot, we investigated the KLF5 expression changes in a myocardial infarction (MI) mouse model and heart tissue from patients with ischemic heart failure. Using 2D echocardiography, we evaluated the effect of KLF5 inhibition after MI using pharmacological KLF5 inhibitor ML264 and mice with cardiomyocyte-specific KLF5 deletion (αMHC [α-myosin heavy chain]-KLF5 KLF5 mRNA and protein levels were higher in human ischemic heart failure samples and in rodent models at 24 hours, 2 weeks, and 4 weeks post-permanent left coronary artery ligation. αMHC-KLF5 KLF5 is induced during the development of ischemic heart failure in humans and mice and stimulates ceramide biosynthesis. Genetic or pharmacological inhibition of KLF5 in mice with MI prevents ceramide accumulation, alleviates eccentric remodeling, and increases ejection fraction. Thus, KLF5 emerges as a novel therapeutic target for the treatment of ischemic heart failure.

Sections du résumé

BACKGROUND
We previously showed that cardiomyocyte Krϋppel-like factor (KLF) 5 regulates cardiac fatty acid oxidation. As heart failure has been associated with altered fatty acid oxidation, we investigated the role of cardiomyocyte KLF5 in lipid metabolism and pathophysiology of ischemic heart failure.
METHODS
Using real-time polymerase chain reaction and Western blot, we investigated the KLF5 expression changes in a myocardial infarction (MI) mouse model and heart tissue from patients with ischemic heart failure. Using 2D echocardiography, we evaluated the effect of KLF5 inhibition after MI using pharmacological KLF5 inhibitor ML264 and mice with cardiomyocyte-specific KLF5 deletion (αMHC [α-myosin heavy chain]-KLF5
RESULTS
KLF5 mRNA and protein levels were higher in human ischemic heart failure samples and in rodent models at 24 hours, 2 weeks, and 4 weeks post-permanent left coronary artery ligation. αMHC-KLF5
CONCLUSIONS
KLF5 is induced during the development of ischemic heart failure in humans and mice and stimulates ceramide biosynthesis. Genetic or pharmacological inhibition of KLF5 in mice with MI prevents ceramide accumulation, alleviates eccentric remodeling, and increases ejection fraction. Thus, KLF5 emerges as a novel therapeutic target for the treatment of ischemic heart failure.

Identifiants

DOI: 10.1161/CIRCULATIONAHA.120.047420 PMID: 33430631 PMC: PMC7965352
pubmed: 33430631
doi: 10.1161/CIRCULATIONAHA.120.047420
pmc: PMC7965352
mid: NIHMS1671529
doi:

Substances chimiques

Ceramides 0
Kruppel-Like Transcription Factors 0

Types de publication

Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

1139-1156

Subventions

Organisme : NIGMS NIH HHS
ID : R01 GM135399
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL130218
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL151924
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL073029
Pays : United States
Organisme : NHLBI NIH HHS
ID : P01 HL147841
Pays : United States
Organisme : NHLBI NIH HHS
ID : F30 HL146007
Pays : United States

Références

Cardiovasc Res. 2011 Jan 1;89(1):148-56
pubmed: 20729341
Cell Signal. 2008 Jun;20(6):1010-8
pubmed: 18191382
N Engl J Med. 2007 Mar 15;356(11):1140-51
pubmed: 17360992
J Cardiovasc Pharmacol. 2009 Mar;53(3):198-208
pubmed: 19247196
Nat Rev Endocrinol. 2015 Oct;11(10):617-25
pubmed: 26303601
J Mol Cell Cardiol. 2005 Jul;39(1):133-47
pubmed: 15913645
J Biol Chem. 2014 Oct 24;289(43):29881-91
pubmed: 25157099
Circulation. 2007 Jul 24;116(4):434-48
pubmed: 17646594
Nature. 1996 Mar 7;380(6569):75-9
pubmed: 8598911
Mol Cancer Ther. 2016 Jan;15(1):72-83
pubmed: 26621868
JACC Cardiovasc Imaging. 2009 May;2(5):592-9
pubmed: 19442946
Physiol Rev. 2010 Oct;90(4):1337-81
pubmed: 20959618
J Lipid Res. 2008 Oct;49(10):2101-12
pubmed: 18515784
J Clin Invest. 2011 Jul;121(7):2625-40
pubmed: 21670500
J Cell Sci. 2006 Sep 1;119(Pt 17):3593-601
pubmed: 16912082
Basic Res Cardiol. 2016 Mar;111(2):12
pubmed: 26786259
Diabetes. 2013 Jan;62(1):1-8
pubmed: 23258903
Biochim Biophys Acta Mol Basis Dis. 2019 Sep 1;1865(9):2125-2137
pubmed: 31029826
J Biol Chem. 1998 Jun 5;273(23):14550-9
pubmed: 9603970
Endocr Rev. 2019 Feb 1;40(1):137-152
pubmed: 30307551
Curr Heart Fail Rep. 2013 Jun;10(2):109-21
pubmed: 23508767
Development. 2010 Dec;137(23):3953-63
pubmed: 20980403
Circ Res. 2016 Jan 22;118(2):241-53
pubmed: 26574507
PLoS One. 2015 Aug 10;10(8):e0135228
pubmed: 26258408
Front Cardiovasc Med. 2018 Jun 06;5:68
pubmed: 29928647
JACC Basic Transl Sci. 2018 Feb;3(1):132-156
pubmed: 29876529
Circ Res. 2010 Dec 10;107(12):1445-53
pubmed: 20966393
Biochim Biophys Acta. 2002 Dec 30;1585(2-3):114-25
pubmed: 12531544
Proc Natl Acad Sci U S A. 2000 Feb 15;97(4):1784-9
pubmed: 10677535
Heart Fail Clin. 2012 Oct;8(4):633-41
pubmed: 22999245
Proc Natl Acad Sci U S A. 1998 Mar 17;95(6):2979-84
pubmed: 9501201
Nucleic Acids Res. 2015 Jul 1;43(W1):W566-70
pubmed: 25969447
Circulation. 2020 Mar 17;141(11):916-930
pubmed: 31992066
Circulation. 2008 Mar 25;117(12):1610-9
pubmed: 18299505
JCI Insight. 2017 Jul 20;2(14):
pubmed: 28724803
FASEB J. 2007 Feb;21(2):543-50
pubmed: 17158781
Circulation. 1998 Nov 24;98(21):2227-34
pubmed: 9867443
J Biol Chem. 2009 Dec 25;284(52):36312-23
pubmed: 19778901
J Clin Invest. 2000 Aug;106(4):589-97
pubmed: 10953034
J Biol Chem. 2007 Apr 13;282(15):11549-61
pubmed: 17303575
Circ Res. 2013 Aug 16;113(5):603-16
pubmed: 23948585
Nat Med. 2002 Aug;8(8):856-63
pubmed: 12101409
J Am Heart Assoc. 2019 May 21;8(10):e012260
pubmed: 31112430
J Am Heart Assoc. 2016 Sep 16;5(9):
pubmed: 27638782
J Clin Invest. 2010 Jan;120(1):254-65
pubmed: 20038803
Front Cardiovasc Med. 2018 Jun 11;5:69
pubmed: 29942807
Am J Physiol Heart Circ Physiol. 2009 Dec;297(6):H2096-108
pubmed: 19801494
Cell Death Dis. 2019 Dec 2;10(12):908
pubmed: 31787746
J Biol Chem. 1997 Apr 25;272(17):11369-77
pubmed: 9111045

Auteurs

Matthew Hoffman (M)

Center for Translational Medicine, Lewis Katz School of Medicine at Temple University, Philadelphia, PA (M.H., D.P., I.D.K., C.M., S.R., E.G., R.K., K.D.).

Dimitra Palioura (D)

Center for Translational Medicine, Lewis Katz School of Medicine at Temple University, Philadelphia, PA (M.H., D.P., I.D.K., C.M., S.R., E.G., R.K., K.D.).

Ioannis D Kyriazis (ID)

Center for Translational Medicine, Lewis Katz School of Medicine at Temple University, Philadelphia, PA (M.H., D.P., I.D.K., C.M., S.R., E.G., R.K., K.D.).

Maria Cimini (M)

Center for Translational Medicine, Lewis Katz School of Medicine at Temple University, Philadelphia, PA (M.H., D.P., I.D.K., C.M., S.R., E.G., R.K., K.D.).

Rachit Badolia (R)

Nora Eccles Harrison Cardiovascular Research and Training Institute, Division of Cardiovascular Medicine (S.G.D., R.B.), Salt Lake City, UT.

Sudarsan Rajan (S)

Center for Translational Medicine, Lewis Katz School of Medicine at Temple University, Philadelphia, PA (M.H., D.P., I.D.K., C.M., S.R., E.G., R.K., K.D.).

Erhe Gao (E)

Center for Translational Medicine, Lewis Katz School of Medicine at Temple University, Philadelphia, PA (M.H., D.P., I.D.K., C.M., S.R., E.G., R.K., K.D.).

Nikolas Nikolaidis (N)

Department of Biological Science, Center for Applied Biotechnology Studies, and Center for Computational and Applied Mathematics, College of Natural Sciences and Mathematics, California State University Fullerton (N.N.).

P Christian Schulze (PC)

Department of Internal Medicine, Division of Cardiology, Angiology, Intensive Medical Care, and Pneumology, University Hospital Jena, Germany (P.C.S.).

Ira J Goldberg (IJ)

Division of Endocrinology, Diabetes and Metabolism, New York University School of Medicine (I.J.G.).

Raj Kishore (R)

Center for Translational Medicine, Lewis Katz School of Medicine at Temple University, Philadelphia, PA (M.H., D.P., I.D.K., C.M., S.R., E.G., R.K., K.D.).

Vincent W Yang (VW)

School of Medicine, Stony Brook University, NY (V.W.Y., A.B.).

Thomas D Bannister (TD)

The Scripps Research Institute, Jupiter, FL (T.D.B.).

Agnieszka B Bialkowska (AB)

School of Medicine, Stony Brook University, NY (V.W.Y., A.B.).

Craig H Selzman (CH)

Division of Cardiothoracic Surgery (C.H.S.), Salt Lake City, UT.

Stavros G Drakos (SG)

Nora Eccles Harrison Cardiovascular Research and Training Institute, Division of Cardiovascular Medicine (S.G.D., R.B.), Salt Lake City, UT.

Konstantinos Drosatos (K)

Center for Translational Medicine, Lewis Katz School of Medicine at Temple University, Philadelphia, PA (M.H., D.P., I.D.K., C.M., S.R., E.G., R.K., K.D.).

Articles similaires

[Redispensing of expensive oral anticancer medicines: a practical application].

Lisanne N van Merendonk, Kübra Akgöl, Bastiaan Nuijen
1.00
Humans Antineoplastic Agents Administration, Oral Drug Costs Counterfeit Drugs

Smoking Cessation and Incident Cardiovascular Disease.

Jun Hwan Cho, Seung Yong Shin, Hoseob Kim et al.
1.00
Humans Male Smoking Cessation Cardiovascular Diseases Female

Evaluation of Low-Value Services Across Major Medicare Advantage Insurers and Traditional Medicare.

Ciara Duggan, Adam L Beckman, Ishani Ganguli et al.
1.00
Humans United States Aged Cross-Sectional Studies Medicare Part C

Effectiveness of Virtual Yoga for Chronic Low Back Pain: A Randomized Clinical Trial.

Hallie Tankha, Devyn Gaskins, Amanda Shallcross et al.
1.00
Humans Yoga Low Back Pain Female Male

Classifications MeSH

questionsmedicales.fr › Eucaryotes › Animaux › Cardiomyocyte Krüppel-Like Factor 5 Promotes...
questionsmedicales.fr › Maladies cardiovasculaires › Cardiopathies › Cardiomyopathies › Cardiomyocyte Krüppel-Like Factor 5 Promotes...
questionsmedicales.fr › Lipides › Lipides membranaires › Sphingolipides › Glycosphingolipides › Glycosphingolipides neutres › Céramides › Cardiomyocyte Krüppel-Like Factor 5 Promotes...
questionsmedicales.fr › Techniques d'investigation › Modèles théoriques › Modèles biologiques › Modèles animaux de maladie humaine › Cardiomyocyte Krüppel-Like Factor 5 Promotes...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › Cardiomyocyte Krüppel-Like Factor 5 Promotes...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Facteurs de transcription › Facteurs de transcription Krüppel-like › Cardiomyocyte Krüppel-Like Factor 5 Promotes...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Rodentia › Muridae › Murinae › Souris › Cardiomyocyte Krüppel-Like Factor 5 Promotes...
questionsmedicales.fr › Cellules › Cellules musculaires › Myocytes cardiaques › Cardiomyocyte Krüppel-Like Factor 5 Promotes...
questionsmedicales.fr › Phénomènes physiologiques respiratoires et circulatoires › Phénomènes physiologiques cardiovasculaires › Fonction ventriculaire › Remodelage ventriculaire › Cardiomyocyte Krüppel-Like Factor 5 Promotes...