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Review
. 2010 Oct;20(7):217-21.
doi: 10.1016/j.tcm.2011.11.002.

Mitogen-activated protein kinase inhibitor regulation of heart function and fibrosis in cardiomyopathy caused by lamin A/C gene mutation

Antoine Muchir  1 , Wei Wu, Howard J Worman
Affiliations
Review

Mitogen-activated protein kinase inhibitor regulation of heart function and fibrosis in cardiomyopathy caused by lamin A/C gene mutation

Antoine Muchir et al. Trends Cardiovasc Med. 2010 Oct.

Abstract

Mutations in the lamin A/C gene (LMNA) encoding A-type nuclear lamins cause dilated cardiomyopathy. We have uncovered a novel connection between these mutations and hyperactivation of the extracellular signal-regulated kinase 1/2 and c-jun N-terminal kinase branches of the mitogen-activated protein kinase signaling pathway in a mouse model of the disease. This discovery has identified targets that can be inhibited by drugs that improve heart function and prevent fibrosis.

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Conflict of interest statement

Potential Conflict of Interest

Drs. Worman and Muchir are inventors on a pending PCT patent application on methods for treating and/or preventing cardiomyopathies by ERK and JNK inhibition filed by the trustees of Columbia University in the City of New York.

Figures

Figure 1
Figure 1
Diagram of molecular and cellular events linking an Lmna point mutation in mice to MAP kinase activation and the development of cardiomyopathy. In Lmna+/+ mice (upper right), baseline ERK1/2 (ERK) and JNK signaling maintain normal cardiac function. In LmnaH222P/H222P mice (upper left), there is hyper-activation of ERK1/2 and JNK signaling, leading to induction of a “fetal gene program” and myocardial fibrosis that over time results in cardiomyopathy. Treatment of LmnaH222P/H222P mice with inhibitors of ERK1/2 and JNK signaling (bottom) reverse induced elements of the “fetal gene program” and prevent myocardial fibrosis, leading to improved cardiac function.
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References

    1. Adjei AA, Cohen RB, Franklin W, et al. Phase I pharmacokinetics and pharmacodynamics study of the oral, small-molecule mitogen-activated protein kinase kinase 1/2 inhibitor AZD6244 (ARRY-142886) in patients with advanced cancers. J Clin Oncol. 2008;26:2139–2146. - PMC - PubMed
    1. Aebi U, Cohn J, Buhle L, Gerace L. The nuclear lamina is a meshwork of intermediate-type filaments. Nature. 1986;323:560–564. - PubMed
    1. Arimura T, Helbling-Leclerc A, Massart C, et al. Mouse model carrying H222P-Lmna mutation develops muscular dystrophy and dilated cardiomyopathy similar to human striated muscle laminopathies. Hum Mol Genet. 2005;14:155–169. - PubMed
    1. Bekaii-Saab T, Phelps MA, Li X, et al. Multi-institutional phase II study of selumetinib in patients with metastatic biliary cancer. J Clin Oncol. 2011;29:2357–2363. - PMC - PubMed
    1. Ben Yaou R, Gueneau L, Demay L, et al. Heart involvement in lamin A/C related diseases. Arch Mal Coeur Vaiss. 2006;99:848–855. - PubMed

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