CoChat
Sign Up
Cited by 35Cardiac Fibrosis and RemodelingCongenital heart defects researchCardiomyopathy and Myosin Studies

Postnatal Ablation of Foxm1 from Cardiomyocytes Causes Late Onset Cardiac Hypertrophy and Fibrosis without Exacerbating Pressure Overload-Induced Cardiac Remodeling

Open access
Bolte, Craig, Zhang, Yufang, York, Allen, Kalin, Tanya V., Schultz, Jo El J., Molkentin, Jeffery D., Kalinichenko, Vladimir V.·2012·PLoS ONE
DOI 10.1371/journal.pone.0048713PMC PMC3493600
Open this paper in CoChat — free accountOpen PDF

Abstract

Heart disease remains a leading cause of morbidity and mortality in the industrialized world. Hypertrophic cardiomyopathy is the most common genetic cardiovascular disorder and the most common cause of sudden cardiac death. Foxm1 transcription factor (also known as HFH-11B, Trident, Win or MPP2) plays an important role in the pathogenesis of various cancers and is a critical mediator of post-injury repair in multiple organs. Foxm1 has been previously shown to be essential for heart development and proliferation of embryonic cardiomyocytes. However, the role of Foxm1 in postnatal heart development and in cardiac injury has not been evaluated. To delete Foxm1 in postnatal cardiomyocytes, αMHC-Cre/Foxm1(fl/fl) mice were generated. Surprisingly, αMHC-Cre/Foxm1(fl/fl) mice exhibited normal cardiomyocyte proliferation at postnatal day seven and had no defects in cardiac structure or function but developed cardiac hypertrophy and fibrosis late in life. The development of cardiomyocyte hypertrophy and cardiac fibrosis in aged Foxm1-deficient mice was associated with reduced expression of Hey2, an important regulator of cardiac homeostasis, and increased expression of genes critical for cardiac remodeling, including MMP9, αSMA, fibronectin and vimentin. We also found that following aortic constriction Foxm1 mRNA and protein were induced in cardiomyocytes. However, Foxm1 deletion did not exacerbate cardiac hypertrophy or fibrosis following chronic pressure overload. Our results demonstrate that Foxm1 regulates genes critical for age-induced cardiomyocyte hypertrophy and cardiac fibrosis.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1371/journal.pone.0048713

Cites

1 of 1 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Among the top 25 deleted genes with the most significant effect were transcription factors known to regulate myocardial development (e.g. FOXM1) and entirely novel dosage-sensitive gene candidates such as TEAD4.

    “Among the top 25 deleted genes with the most significant effect were transcription factors known to regulate myocardial development (e.g. FOXM125,26) and entirely novel dosage-sensitive gene candidates such as TEAD4 (Supplementary Table 3).”

    From Transfer learning enables predictions in network biology (2023) · cites this paper as [26]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Cites

Flagged first, then by citations

Research works printed but not linked: 41

  1. [1]Raju H, Alberg C, Sagoo GS, Burton H, Behr ER (2011) Inherited cardiomyopathies. BMJ 343: d6966. 22106372
  2. [2]Semsarian C (2011) Guidelines for the diagnosis and management of hypertrophic cardiomyopathy. Heart Lung Circ 20: 688– 690. 22000299
  3. [3]Bowles NE, Towbin JA (1998) Molecular aspects of myocarditis. Curr Opin Cardiol 13: 179– 184. 9649940
  4. [4]Gaschen L, Lang J, Lin S, Ade-Damilano M, Busato A, et al (1999) Cardiomyopathy in dystrophin-deficient hypertrophic feline muscular dystrophy. J Vet Intern Med 13: 346– 356. 10449227
  5. [5]Kapelko VI (2001) Extracellular matrix alterations in cardiomyopathy: The possible crucial role in the dilative form. Exp Clin Cardiol 6: 41– 49. 20428444 PMC2858965
  6. [6]Korver W, Roose J, Clevers H (1997) The winged-helix transcription factor Trident is expressed in cycling cells. Nucleic Acids Res 25: 1715– 1719. 9108152 PMC146663
  7. [7]Ye H, Holterman AX, Yoo KW, Franks RR, Costa RH (1999) Premature expression of the winged helix transcription factor HFH-11B in regenerating mouse liver accelerates hepatocyte entry into S phase. Mol Cell Biol 19: 8570– 8580. 10567581 PMC84981
  8. [8]Ly DH, Lockhart DJ, Lerner RA, Schultz PG (2000) Mitotic misregulation and human aging. Science 287: 2486– 2492. 10741968
  9. [9]Wang X, Quail E, Hung NJ, Tan Y, Ye H, et al (2001) Increased levels of forkhead box M1B transcription factor in transgenic mouse hepatocytes prevent age-related proliferation defects in regenerating liver. Proc Natl Acad Sci U S A 98: 11468– 11473. 11572993 PMC58753
  10. [11]Ramakrishna S, Kim IM, Petrovic V, Malin D, Wang IC, et al (2007) Myocardium defects and ventricular hypoplasia in mice homozygous null for the Forkhead Box M1 transcription factor. Dev Dyn 236: 1000– 1013. 17366632
  11. [12]Korver W, Schilham MW, Moerer P, van den Hoff MJ, Dam K, et al (1998) Uncoupling of S phase and mitosis in cardiomyocytes and hepatocytes lacking the winged-helix transcription factor Trident. Curr Biol 8: 1327– 1330. 9843684
  12. [13]Kokubo H, Miyagawa-Tomita S, Tomimatsu H, Nakashima Y, Nakazawa M, et al (2004) Targeted disruption of hesr2 results in atrioventricular valve anomalies that lead to heart dysfunction. Circ Res 95: 540– 547. 15297376
  13. [14]Krupczak-Hollis K, Wang X, Kalinichenko VV, Gusarova GA, Wang IC, et al (2004) The mouse Forkhead Box m1 transcription factor is essential for hepatoblast mitosis and development of intrahepatic bile ducts and vessels during liver morphogenesis. Dev Biol 276: 74– 88. 15531365
  14. [15]Palermo J, Gulick J, Colbert M, Fewell J, Robbins J (1996) Transgenic remodeling of the contractile apparatus in the mammalian heart. Circ Res 78: 504– 509. 8593710
  15. [16]Schultz Jel J, Witt SA, Glascock BJ, Nieman ML, Reiser PJ, et al (2002) TGF-beta1 mediates the hypertrophic cardiomyocyte growth induced by angiotensin II. J Clin Invest 109: 787– 796. 11901187 PMC150912
  16. [17]Nakayama H, Wilkin BJ, Bodi I, Molkentin JD (2006) Calcineurin-dependent cardiomyopathy is activated by TRPC in the adult mouse heart. FASEB J 20: 1660– 1670. 16873889 PMC2693319
  17. [18]Oka T, Maillet M, Watt AJ, Schwartz RJ, Aronow BJ, et al (2006) Cardiac-specific deletion of Gata4 reveals its requirement for hypertrophy, compensation, and myocyte viability. Circ Res 98: 837– 845. 16514068
  18. [19]Kalin TV, Wang IC, Meliton L, Zhang Y, Wert SE, et al (2008) Forkhead Box m1 transcription factor is required for perinatal lung function. Proc Natl Acad Sci U S A 105: 19330– 19335. 19033457 PMC2587228
  19. [20]Kim IM, Zhou Y, Ramakrishna S, Hughes DE, Solway J, et al (2005) Functional characterization of evolutionarily conserved DNA regions in forkhead box f1 gene locus. J Biol Chem 280: 37908– 37916. 16144835
  20. [21]Kim IM, Ramakrishna S, Gusarova GA, Yoder HM, Costa RH, et al (2005) The forkhead box m1 transcription factor is essential for embryonic development of pulmonary vasculature. J Biol Chem 280: 22278– 22286. 15817462
  21. [22]Ustiyan V, Wang IC, Ren X, Zhang Y, Snyder J, et al (2009) Forkhead box M1 transcriptional factor is required for smooth muscle cells during embryonic development of blood vessels and esophagus. Dev Biol 336: 266– 279. 19835856 PMC2783468
  22. [23]Wang IC, Meliton L, Ren X, Zhang Y, Balli D, et al (2009) Deletion of Forkhead Box M1 transcription factor from respiratory epithelial cells inhibits pulmonary tumorigenesis. PLoS One 4: e6609. 19672312 PMC2720537
  23. [24]Murakami H, Aiba H, Nakanishi M, Murakami-Tonami Y (2010) Regulation of yeast forkhead transcription factors and FoxM1 by cyclin-dependent and polo-like kinases. Cell Cycle 9: 3233– 3242. 20716958
  24. [25]Liu Y, Yu M, Wu L, Chin MT (2010) The bHLH transcription factor CHF1/Hey2 regulates susceptibility to apoptosis and heart failure after pressure overload. Am J Physiol Heart Circ Physiol 298: H2082– 2092. 20382855 PMC2886641
  25. [26]Yu M, Liu Y, Xiang F, Li Y, Cullen D, et al (2009) CHF1/Hey2 promotes physiological hypertrophy in response to pressure overload through selective repression and activation of specific transcriptional pathways. OMICS 13: 501– 511. 20001863 PMC3145963
  26. [27]Ng WA, Grupp IL, Subramaniam A, Robbins J (1991) Cardiac myosin heavy chain mRNA expression and myocardial function in the mouse heart. Circ Res 68: 1742– 1750. 2036722
  27. [28]Sakata Y, Koibuchi N, Xiang F, Youngblood JM, Kamei CN, et al (2006) The spectrum of cardiovascular anomalies in CHF1/Hey2 deficient mice reveals roles in endocardial cushion, myocardial and vascular maturation. J Mol Cell Cardiol 40: 267– 273. 16242143
  28. [29]Niessen K, Karsan A (2008) Notch signaling in cardiac development. Circ Res 102: 1169– 1181. 18497317
  29. [30]Kalinichenko VV, Gusarova GA, Tan Y, Wang IC, Major ML, et al (2003) Ubiquitous expression of the forkhead box M1B transgene accelerates proliferation of distinct pulmonary cell types following lung injury. J Biol Chem 278: 37888– 37894. 12867420
  30. [31]Kalinichenko VV, Lim L, Shin B, Costa RH (2001) Differential expression of forkhead box transcription factors following butylated hydroxytoluene lung injury. Am J Physiol Lung Cell Mol Physiol 280: L695– 704. 11238010
  31. [32]Ren X, Zhang Y, Snyder J, Cross ER, Shah TA, et al (2010) Forkhead box M1 transcription factor is required for macrophage recruitment during liver repair. Mol Cell Biol 30: 5381– 5393. 20837707 PMC2976366
  32. [33]Schuller U, Zhao Q, Godinho SA, Heine VM, Medema RH, et al (2007) Forkhead transcription factor FoxM1 regulates mitotic entry and prevents spindle defects in cerebellar granule neuron precursors. Mol Cell Biol 27: 8259– 8270. 17893320 PMC2169184
  33. [34]Xue L, Chiang L, He B, Zhao YY, Winoto A (2010) FoxM1, a forkhead transcription factor is a master cell cycle regulator for mouse mature T cells but not double positive thymocytes. PLoS One 5: e9229. 20169079 PMC2821927
  34. [35]Zhang H, Ackermann AM, Gusarova GA, Lowe D, Feng X, et al (2006) The FoxM1 transcription factor is required to maintain pancreatic beta-cell mass. Mol Endocrinol 20: 1853– 1866. 16556734
  35. [36]Zhang H, Zhang J, Pope CF, Crawford LA, Vasavada RC, et al (2010) Gestational diabetes mellitus resulting from impaired beta-cell compensation in the absence of FoxM1, a novel downstream effector of placental lactogen. Diabetes 59: 143– 152. 19833884 PMC2797915
  36. [37]Zhao YY, Gao XP, Zhao YD, Mirza MK, Frey RS, et al (2006) Endothelial cell-restricted disruption of FoxM1 impairs endothelial repair following LPS-induced vascular injury. J Clin Invest 116: 2333– 2343. 16955137 PMC1555637
  37. [38]Maron BJ, Casey SA, Hauser RG, Aeppli DM (2003) Clinical course of hypertrophic cardiomyopathy with survival to advanced age. J Am Coll Cardiol 42: 882– 888. 12957437
  38. [39]Niimura H, Bachinski LL, Sangwatanaroj S, Watkins H, Chudley AE, et al (1998) Mutations in the gene for cardiac myosin-binding protein C and late-onset familial hypertrophic cardiomyopathy. N Engl J Med 338: 1248– 1257. 9562578
  39. [40]Kubo T, Kitaoka H, Okawa M, Nishinaga M, Doi YL (2010) Hypertrophic cardiomyopathy in the elderly. Geriatr Gerontol Int 10: 9– 16. 20102377
  40. [41]Ommen SR (2011) Hypertrophic cardiomyopathy. Curr Probl Cardiol 36: 409– 453. 21962729
  41. [42]Sakamoto A, Ono K, Abe M, Jasmin G, Eki T, et al (1997) Both hypertrophic and dilated cardiomyopathies are caused by mutation of the same gene, delta-sarcoglycan, in hamster: an animal model of disrupted dystrophin-associated glycoprotein complex. Proc Natl Acad Sci U S A 94: 13873– 13878. 9391120 PMC28400

Cited by

Sorted by citations

Authors
Bolte, C., Zhang, Y., York, A., Kalin, T. V., Schultz, J. E. J., Molkentin, J. D., & Kalinichenko, V. V.
Affiliations
  • Cincinnati Children's Hospital Medical Center (US)
  • University of Cincinnati (US)
Corresponding author
  • Bolte, Craig
  • Kalinichenko, Vladimir V.
ORCID
Venue
PLoS ONE
Publisher
Public Library of Science (PLoS)
Published
2012-11-08
Volume
7
Issue
11
Pages
e48713
ISSN
1932-6203 (ISSN-L)
DOI
10.1371/journal.pone.0048713
PMC
PMC3493600
OpenAlex
W2014543194
Cited by
35
References
1
Citations by year
2026: 1 · 2025: 2 · 2024: 3 · 2023: 2 · 2022: 3 · 2021: 5 · 2020: 1 · 2019: 4 · 2018: 3 · 2017: 5 · 2016: 2 · 2015: 2 · 2014: 1 · 2013: 1
FWCI
0.82
Type
journal article
Language
en
Open access
Licence
Locations
  • PLoS ONE (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
National Heart, Lung, and Blood Institute (R01 HL 84151, R01HL084151)
Topics
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac Fibrosis and Remodeling
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Congenital heart defects research
  • Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiomyopathy and Myosin Studies
Keywords
FOXM1, cardiomyocytes, cardiac hypertrophy, myocardial fibrosis, cardiac remodeling, pressure overload, aortic constriction, Hey2, hypertrophic cardiomyopathy, postnatal heart development, cardiac injury, MMP-9, alpha-smooth muscle actin, fibronectin, vimentin
MeSH terms
Forkhead Box Protein M1, Actins, Age Factors, Animals, Fibronectins, Fibrosis, Heart, Cardiomegaly, Mice, Transgenic, Myocardium, Repressor Proteins, Vimentin, Gene Expression Regulation, Developmental, Matrix Metalloproteinase 9, Myocytes, Cardiac, Cell Proliferation, Mice, Basic Helix-Loop-Helix Proteins, Basic Helix-Loop-Helix Transcription Factors, Forkhead Transcription Factors

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review