MAPK Signalling in Cardiovascular Health and Disease: Molecular Mechanisms and Therapeutic Targets

Overview

Journal Clin Sci (Lond)

Specialties Biochemistry
General Medicine
Science

Date 2008 Aug 30

PMID 18752467

Citations 209

Authors

Anthony J Muslin

Affiliations

Soon will be listed here.

Abstract

Intracellular MAPK (mitogen-activated protein kinase) signalling cascades probably play an important role in the pathogenesis of cardiac and vascular disease. A substantial amount of basic science research has defined many of the details of MAPK pathway organization and activation, but the role of individual signalling proteins in the pathogenesis of various cardiovascular diseases is still being elucidated. In the present review, the role of the MAPKs ERK (extracellular signal-regulated kinase), JNK (c-Jun N-terminal kinase) and p38 MAPK in cardiac hypertrophy, cardiac remodelling after myocardial infarction, atherosclerosis and vascular restenosis will be examined, with attention paid to genetically modified murine model systems and to the use of pharmacological inhibitors of protein kinases. Despite the complexities of this field of research, attractive targets for pharmacological therapy are emerging.

Citing Articles

Deciphering Oxidative Stress in Cardiovascular Disease Progression: A Blueprint for Mechanistic Understanding and Therapeutic Innovation.

Zhang Z, Guo J Antioxidants (Basel). 2025; 14(1).

PMID: 39857372 PMC: 11759168. DOI: 10.3390/antiox14010038.

Traditional Chinese medicine in the treatment of -related gastritis: The mechanisms of signalling pathway regulations.

Zhang P, Li L, Qu H, Chen G, Xie M, Chen Y World J Gastroenterol. 2025; 31(3):96582.

PMID: 39839895 PMC: 11684169. DOI: 10.3748/wjg.v31.i3.96582.

Impact of statin therapy on CD40:CD40L signaling: mechanistic insights and therapeutic opportunities.

Askarizadeh F, Karav S, Jamialahmadi T, Sahebkar A Pharmacol Rep. 2024; 77(1):43-71.

PMID: 39680334 DOI: 10.1007/s43440-024-00678-2.

Contribution of rare chromosome 22q11.2 copy number variants to non-syndromic bicuspid aortic valve.

DiGregorio H, Mansoorshahi S, Carlisle S, Tovar Pensa C, Watts A, McNeely C Heart. 2024; 111(5):221-229.

PMID: 39658198 PMC: 11821425. DOI: 10.1136/heartjnl-2024-324669.

Oxidized Low-Density Lipoprotein and Its Role in Immunometabolism.

Mosalmanzadeh N, Pence B Int J Mol Sci. 2024; 25(21).

PMID: 39518939 PMC: 11545486. DOI: 10.3390/ijms252111386.

References

Rockman H, Wachhorst S, Mao L, ROSS Jr J . ANG II receptor blockade prevents ventricular hypertrophy and ANF gene expression with pressure overload in mice. Am J Physiol. 1994; 266(6 Pt 2):H2468-75. DOI: 10.1152/ajpheart.1994.266.6.H2468. View

Zhao M, Liu Y, Wang X, New L, Han J, Brunk U . Activation of the p38 MAP kinase pathway is required for foam cell formation from macrophages exposed to oxidized LDL. APMIS. 2002; 110(6):458-68. DOI: 10.1034/j.1600-0463.2002.100604.x. View

Ichijo H, Nishida E, Irie K, Ten Dijke P, Saitoh M, Moriguchi T . Induction of apoptosis by ASK1, a mammalian MAPKKK that activates SAPK/JNK and p38 signaling pathways. Science. 1997; 275(5296):90-4. DOI: 10.1126/science.275.5296.90. View

Tsujita Y, Muraski J, Shiraishi I, Kato T, Kajstura J, Anversa P . Nuclear targeting of Akt antagonizes aspects of cardiomyocyte hypertrophy. Proc Natl Acad Sci U S A. 2006; 103(32):11946-51. PMC: 1567678. DOI: 10.1073/pnas.0510138103. View

Tiwari R, Singh V, Barthwal M . Macrophages: an elusive yet emerging therapeutic target of atherosclerosis. Med Res Rev. 2007; 28(4):483-544. DOI: 10.1002/med.20118. View

Chardin P, Camonis J, Gale N, Van Aelst L, Schlessinger J, Wigler M . Human Sos1: a guanine nucleotide exchange factor for Ras that binds to GRB2. Science. 1993; 260(5112):1338-43. DOI: 10.1126/science.8493579. View

Proctor B, Ren J, Chen Z, Schneider J, Coleman T, Lupu T . Grb2 is required for atherosclerotic lesion formation. Arterioscler Thromb Vasc Biol. 2007; 27(6):1361-7. DOI: 10.1161/ATVBAHA.106.134007. View

Wetzker R, Bohmer F . Transactivation joins multiple tracks to the ERK/MAPK cascade. Nat Rev Mol Cell Biol. 2003; 4(8):651-7. DOI: 10.1038/nrm1173. View

Tenhunen O, Soini Y, Ilves M, Rysa J, Tuukkanen J, Serpi R . p38 Kinase rescues failing myocardium after myocardial infarction: evidence for angiogenic and anti-apoptotic mechanisms. FASEB J. 2006; 20(11):1907-9. DOI: 10.1096/fj.05-5618fje. View

10.

Tsakiridis T, Taha C, Grinstein S, Klip A . Insulin activates a p21-activated kinase in muscle cells via phosphatidylinositol 3-kinase. J Biol Chem. 1996; 271(33):19664-7. DOI: 10.1074/jbc.271.33.19664. View

11.

Buday L, Downward J . Epidermal growth factor regulates p21ras through the formation of a complex of receptor, Grb2 adapter protein, and Sos nucleotide exchange factor. Cell. 1993; 73(3):611-20. DOI: 10.1016/0092-8674(93)90146-h. View

12.

Urano F, Wang X, Bertolotti A, Zhang Y, Chung P, Harding H . Coupling of stress in the ER to activation of JNK protein kinases by transmembrane protein kinase IRE1. Science. 2000; 287(5453):664-6. DOI: 10.1126/science.287.5453.664. View

13.

Zhang S, Weinheimer C, Courtois M, Kovacs A, Zhang C, Cheng A . The role of the Grb2-p38 MAPK signaling pathway in cardiac hypertrophy and fibrosis. J Clin Invest. 2003; 111(6):833-41. PMC: 153766. DOI: 10.1172/JCI16290. View

14.

Muslin A . Role of raf proteins in cardiac hypertrophy and cardiomyocyte survival. Trends Cardiovasc Med. 2005; 15(6):225-9. DOI: 10.1016/j.tcm.2005.06.008. View

15.

Wang X, Diener K, Jannuzzi D, Trollinger D, Tan T, Lichenstein H . Molecular cloning and characterization of a novel protein kinase with a catalytic domain homologous to mitogen-activated protein kinase kinase kinase. J Biol Chem. 1996; 271(49):31607-11. DOI: 10.1074/jbc.271.49.31607. View

16.

Sanada S, Node K, Minamino T, Takashima S, Ogai A, Asanuma H . Long-acting Ca2+ blockers prevent myocardial remodeling induced by chronic NO inhibition in rats. Hypertension. 2003; 41(4):963-7. DOI: 10.1161/01.HYP.0000062881.36813.7A. View

17.

Chalmers C, Gilley R, March H, Balmanno K, Cook S . The duration of ERK1/2 activity determines the activation of c-Fos and Fra-1 and the composition and quantitative transcriptional output of AP-1. Cell Signal. 2006; 19(4):695-704. DOI: 10.1016/j.cellsig.2006.09.001. View

18.

Saitoh M, Nishitoh H, Fujii M, Takeda K, Tobiume K, Sawada Y . Mammalian thioredoxin is a direct inhibitor of apoptosis signal-regulating kinase (ASK) 1. EMBO J. 1998; 17(9):2596-606. PMC: 1170601. DOI: 10.1093/emboj/17.9.2596. View

19.

Rolfe M, McLeod L, Pratt P, Proud C . Activation of protein synthesis in cardiomyocytes by the hypertrophic agent phenylephrine requires the activation of ERK and involves phosphorylation of tuberous sclerosis complex 2 (TSC2). Biochem J. 2005; 388(Pt 3):973-84. PMC: 1183479. DOI: 10.1042/BJ20041888. View

20.

Liao P, Georgakopoulos D, Kovacs A, Zheng M, Lerner D, Pu H . The in vivo role of p38 MAP kinases in cardiac remodeling and restrictive cardiomyopathy. Proc Natl Acad Sci U S A. 2001; 98(21):12283-8. PMC: 59806. DOI: 10.1073/pnas.211086598. View