Molecules linked to Ras signaling as therapeutic targets in cardiac pathologies.
Calcineurin
H-Ras gene
K-Ras gene
MAP kinase
Pathological hypertrophy
Physiological hypertrophy
Ras pathway
Ras-opathies
Journal
Biological research
ISSN: 0717-6287
Titre abrégé: Biol Res
Pays: England
ID NLM: 9308271
Informations de publication
Date de publication:
03 Aug 2021
03 Aug 2021
Historique:
received:
15
01
2021
accepted:
26
06
2021
entrez:
4
8
2021
pubmed:
5
8
2021
medline:
6
8
2021
Statut:
epublish
Résumé
The Ras family of small Guanosine Triphosphate (GTP)-binding proteins (G proteins) represents one of the main components of intracellular signal transduction required for normal cardiac growth, but is also critically involved in the development of cardiac hypertrophy and heart failure. The present review provides an update on the role of the H-, K- and N-Ras genes and their related pathways in cardiac diseases. We focus on cardiac hypertrophy and heart failure, where Ras has been studied the most. We also review other cardiac diseases, like genetic disorders related to Ras. The scope of the review extends from fundamental concepts to therapeutic applications. Although the three Ras genes have a nearly identical primary structure, there are important functional differences between them: H-Ras mainly regulates cardiomyocyte size, whereas K-Ras regulates cardiomyocyte proliferation. N-Ras is the least studied in cardiac cells and is less associated to cardiac defects. Clinically, oncogenic H-Ras causes Costello syndrome and facio-cutaneous-skeletal syndromes with hypertrophic cardiomyopathy and arrhythmias. On the other hand, oncogenic K-Ras and alterations of other genes of the Ras-Mitogen-Activated Protein Kinase (MAPK) pathway, like Raf, cause Noonan syndrome and cardio-facio-cutaneous syndromes characterized by cardiac hypertrophy and septal defects. We further review the modulation by Ras of key signaling pathways in the cardiomyocyte, including: (i) the classical Ras-Raf-MAPK pathway, which leads to a more physiological form of cardiac hypertrophy; as well as other pathways associated with pathological cardiac hypertrophy, like (ii) The SAPK (stress activated protein kinase) pathways p38 and JNK; and (iii) The alternative pathway Raf-Calcineurin-Nuclear Factor of Activated T cells (NFAT). Genetic alterations of Ras isoforms or of genes in the Ras-MAPK pathway result in Ras-opathies, conditions frequently associated with cardiac hypertrophy or septal defects among other cardiac diseases. Several studies underline the potential role of H- and K-Ras as a hinge between physiological and pathological cardiac hypertrophy, and as potential therapeutic targets in cardiac hypertrophy and failure.
Identifiants
pubmed: 34344467
doi: 10.1186/s40659-021-00342-6
pii: 10.1186/s40659-021-00342-6
pmc: PMC8330049
doi:
Substances chimiques
Mitogen-Activated Protein Kinases
EC 2.7.11.24
Types de publication
Journal Article
Review
Langues
eng
Sous-ensembles de citation
IM
Pagination
23Informations de copyright
© 2021. The Author(s).
Références
Future Med Chem. 2011 Oct;3(14):1787-808
pubmed: 22004085
Oncogene. 1997 Sep 4;15(10):1151-9
pubmed: 9294608
Trends Cardiovasc Med. 2004 Feb;14(2):50-5
pubmed: 15030789
Nat Commun. 2017 May 10;8:15090
pubmed: 28489072
J Biol Chem. 1997 May 30;272(22):14057-61
pubmed: 9162028
J Clin Invest. 2010 May;120(5):1506-14
pubmed: 20407209
J Biol Chem. 2003 Feb 14;278(7):4572-81
pubmed: 12458225
Circulation. 2015 Jan 27;131(4):390-400; discussion 400
pubmed: 25369805
J Physiol. 2013 Nov 1;591(21):5337-55
pubmed: 24018949
J Biol Chem. 2001 Feb 2;276(5):3524-30
pubmed: 11044444
J Clin Invest. 2011 Mar;121(3):1026-43
pubmed: 21339643
Circulation. 2002 Oct 15;106(16):2118-24
pubmed: 12379583
Trends Biochem Sci. 2003 Nov;28(11):573-6
pubmed: 14607085
Circ Res. 2000 Oct 27;87(9):731-8
pubmed: 11055975
PLoS One. 2013 Aug 22;8(8):e72430
pubmed: 23991110
Nat Genet. 2010 Jan;42(1):27-9
pubmed: 19966803
J Mol Cell Cardiol. 2011 May;50(5):803-12
pubmed: 21093451
Circ Res. 1998 Sep 21;83(6):594-601
pubmed: 9742054
Circ Res. 1999 Apr 2;84(6):735-40
pubmed: 10189362
Nat Rev Mol Cell Biol. 2009 Jan;10(1):63-73
pubmed: 19197333
Can J Physiol Pharmacol. 2015 Aug;93(8):657-65
pubmed: 26158699
Neurology. 2016 Dec 13;87(24):2575-2584
pubmed: 27956565
J Mol Cell Cardiol. 2008 Dec;45(6):812-20
pubmed: 18722381
Development. 1998 Nov;125(22):4359-67
pubmed: 9778496
J Biol Chem. 2001 Aug 31;276(35):32670-7
pubmed: 11431469
J Hum Hypertens. 2012 Oct;26(10):563-9
pubmed: 22129612
Physiol Rev. 2010 Oct;90(4):1507-46
pubmed: 20959622
J Neural Transm (Vienna). 2016 Oct;123(10):1133-8
pubmed: 27565148
Int J Mol Sci. 2019 Mar 30;20(7):
pubmed: 30935055
J Phys Chem B. 2016 Feb 4;120(4):667-79
pubmed: 26761128
Am J Physiol Heart Circ Physiol. 2007 Sep;293(3):H1662-72
pubmed: 17557924
Circulation. 2004 Aug 10;110(6):718-23
pubmed: 15289381
Mol Cell Biol. 2011 Mar;31(6):1110-20
pubmed: 21245384
Circulation. 2001 Feb 6;103(5):670-7
pubmed: 11156878
Nat Rev Drug Discov. 2014 Nov;13(11):828-51
pubmed: 25323927
Nat Cell Biol. 2004 Sep;6(9):807-8
pubmed: 15340447
Nat Rev Mol Cell Biol. 2013 Jan;14(1):38-48
pubmed: 23258295
Nat Rev Mol Cell Biol. 2003 May;4(5):373-84
pubmed: 12728271
Proc Natl Acad Sci U S A. 1997 Apr 29;94(9):4710-5
pubmed: 9114056
Nat Rev Mol Cell Biol. 2008 Jul;9(7):517-31
pubmed: 18568040
Genes Cancer. 2011 Mar;2(3):216-31
pubmed: 21779495
Am J Physiol Heart Circ Physiol. 2004 Jan;286(1):H424-33
pubmed: 12969887
Hypertension. 1998 Oct;32(4):668-75
pubmed: 9774361
Am J Physiol Heart Circ Physiol. 2008 May;294(5):H2406-9
pubmed: 18359895
J Am Coll Cardiol. 2000 May;35(6):1669-77
pubmed: 10807475
Circ Res. 2008 Apr 25;102(8):959-65
pubmed: 18323524
Cell Cycle. 2004 Oct;3(10):1255-8
pubmed: 15467460
Sci Rep. 2017 Feb 22;7:42965
pubmed: 28225023
Am J Med Genet A. 2011 Mar;155A(3):486-507
pubmed: 21344638
Congenit Heart Dis. 2014 Mar-Apr;9(2):144-50
pubmed: 23750712
Circ Heart Fail. 2017 Feb;10(2):
pubmed: 28193718
Int J Cardiol. 2013 Oct 9;168(4):3340-7
pubmed: 23664044
Int J Biochem Cell Biol. 2009 May;41(5):1173-81
pubmed: 19015044
Hypertension. 2007 May;49(5):962-70
pubmed: 17389260
Am J Physiol Heart Circ Physiol. 2002 Aug;283(2):H695-706
pubmed: 12124218
Clin Genet. 2013 Oct;84(4):344-9
pubmed: 23278345
J Physiol. 2017 Jun 15;595(12):4073-4087
pubmed: 28444807
Mol Cell Biol. 2001 Mar;21(5):1444-52
pubmed: 11238881
J Biol Chem. 1993 Jan 25;268(3):2244-9
pubmed: 8420993
Expert Opin Biol Ther. 2010 Jan;10(1):29-41
pubmed: 20078230
Sci Rep. 2016 Dec 23;6:39186
pubmed: 28008986
Circ Res. 2002 Nov 1;91(9):821-9
pubmed: 12411397
Pediatr Cardiol. 2016 Dec;37(8):1539-1547
pubmed: 27554254
EMBO Rep. 2005 May;6(5):432-7
pubmed: 15864294
J Renin Angiotensin Aldosterone Syst. 2001 Mar;2(1_suppl):S154-S161
pubmed: 28095237
Clin Genet. 2008 Jan;73(1):62-70
pubmed: 18042262
J Mol Cell Cardiol. 2008 Apr;44(4):623-32
pubmed: 18339399
Circulation. 2020 Mar 3;141(9):e139-e596
pubmed: 31992061
Nat Genet. 2008 Oct;40(10):1149-50
pubmed: 18818716
Comp Med. 2011 Apr;61(2):109-18
pubmed: 21535921
Cell Oncol. 2010 Jan 1;32(4):245-57
pubmed: 20413844
Pflugers Arch. 2014 Jun;466(6):1163-75
pubmed: 24756197
J Cell Sci. 2005 Mar 1;118(Pt 5):843-6
pubmed: 15731001
Front Biosci. 2000 Apr 01;5:D452-60
pubmed: 10762598
Cell Biochem Funct. 2007 Jul-Aug;25(4):455-61
pubmed: 16850529
Cancer Res. 2012 May 15;72(10):2457-67
pubmed: 22589270
Curr Pharm Des. 2011;17(18):1818-24
pubmed: 21631421
Ann Clin Transl Neurol. 2016 Feb 22;3(4):266-79
pubmed: 27081657
J Am Coll Cardiol. 2018 Jan 16;71(2):201-230
pubmed: 29277252
J Biol Chem. 1998 Aug 21;273(34):21730-5
pubmed: 9705309
Circ Res. 2009 Jul 31;105(3):304-11
pubmed: 19574548
Arch Toxicol. 2015 Sep;89(9):1401-38
pubmed: 25708889
Mol Med. 2012 Sep 07;18:938-47
pubmed: 22576369
J Clin Oncol. 2005 Aug 10;23(23):5281-93
pubmed: 16009947
J Clin Invest. 1999 Aug;104(4):391-8
pubmed: 10449431
J Clin Invest. 2011 Mar;121(3):1009-25
pubmed: 21339642
Circulation. 1997 Oct 7;96(7):2455-61
pubmed: 9337224
J Nucl Cardiol. 2000 Jan-Feb;7(1):63-71
pubmed: 10698236
Heart. 2013 Jul;99(14):992-1003
pubmed: 23349349
Mini Rev Med Chem. 2016;16(5):370-5
pubmed: 26423700
Am J Med Genet C Semin Med Genet. 2020 Mar;184(1):73-80
pubmed: 32022400
J Pharmacol Sci. 2010;113(3):224-33
pubmed: 20562518
J Biol Chem. 1995 Sep 29;270(39):23173-8
pubmed: 7559464
Biochim Biophys Acta. 2014 Nov;1844(11):1970-1976
pubmed: 24881582
J Biol Chem. 2013 Apr 19;288(16):11216-32
pubmed: 23447532
J Clin Invest. 2004 Oct;114(7):937-43
pubmed: 15467832
Oncogene. 2008 May 8;27(21):2961-8
pubmed: 18059342
Clin Exp Pharmacol Physiol. 2007 Apr;34(4):255-62
pubmed: 17324134
Hypertension. 2002 Feb;39(2):233-8
pubmed: 11847190
J Clin Invest. 2011 Mar;121(3):844-7
pubmed: 21339640
Biochim Biophys Acta. 2015 Nov;1853(11 Pt A):2870-84
pubmed: 26260012
Am J Cardiol. 1998 Oct 16;82(8A):2N-9N
pubmed: 9809895
J Mol Cell Cardiol. 2011 Jul;51(1):4-15
pubmed: 21440552
Gene Expr. 1999;7(4-6):337-48
pubmed: 10440234
J Med Genet. 2007 Jul;44(7):e84
pubmed: 17601930
Proc Natl Acad Sci U S A. 2014 Nov 18;111(46):16395-400
pubmed: 25359213
EMBO J. 1996 Feb 15;15(4):775-87
pubmed: 8631299
Mol Cell Biol. 2015 Mar;35(5):831-46
pubmed: 25535334
Future Cardiol. 2007 Jul;3(4):413-23
pubmed: 19804232
J Cardiovasc Dev Dis. 2018 Feb 03;5(1):
pubmed: 29401660
Front Cell Dev Biol. 2021 Feb 11;9:633661
pubmed: 33681212