Cardiomyocyte-Specific Loss of Neurofibromin Promotes Cardiac Hypertrophy and Dysfunction

Xu, Jie; Ismat, Fraz A.; Wang, Tao; Lü, Min; Antonucci, Nicole; Epstein, Jonathan A.

doi:10.1161/circresaha.109.201509

Cited by 41 publications

(32 citation statements)

References 42 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Loss of Nf1 in cardiomyocytes or the endocardial cushions results in heart abnormalities (Gitler et al, 2003;Xu et al, 2009a), but no reports have addressed the disrupted epicardium observed in Nf1-null hearts (Brannan et al, 1994). To determine whether Nf1 has a primary role in epicardial development, we performed in situ hybridization for Nf1 transcripts.…”

Section: Epicardial Inactivation Of Nf1 Results In Aberrant Epicardiumentioning

confidence: 99%

“…It is established that loss of Nf1 leads to prolonged activation of the Ras-MAPK pathway in cardiomyocytes and VSMCs (Cichowski and Jacks, 2001;Xu et al, 2009a;Xu et al, 2007). To determine whether activation of Erk1/2 (Mapk3/1 -Mouse Genome Informatics) is responsible for EMT in Nf1-deficient epicardial cells, we inhibited the MAP kinase pathway and measured EMT by ex vivo migration assay (Mellgren et al, 2008).…”

Section: Nf1 Regulation Of Ras Signaling Plays a Role In Pdgf-inducedmentioning

confidence: 99%

“…Inactivation of Nf1 causes lethality at mid-gestation, with severe heart defects including malformation of the outflow tract, a thinned myocardium, a ventricular septal defect and enlarged endocardial cushions (Brannan et al, 1994;Jacks et al, 1994). Loss of Nf1 in vascular smooth muscle cells (VSMCs) leads to an abnormal proliferative injury response (Xu et al, 2007), and cardiomyocyte-specific inactivation of Nf1 results in pathological hypertrophy and heart failure in adult mice (Xu et al, 2009a). Nf1-null endocardial cushion cells exhibit abnormal EMT (Lakkis and Epstein, 1998), and endothelial-specific deletion of Nf1 recapitulates many of the cardiovascular defects of the Nf1-null mouse, suggesting an indispensable role of Nf1 in endothelial cells during EMT (Gitler et al, 2003).…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Nf1 limits epicardial derivative expansion by regulating epithelial to mesenchymal transition and proliferation

Baek

Tallquist

2012

Development

View full text Add to dashboard Cite

The epicardium is the primary source of coronary vascular smooth muscle cells (cVSMCs) and fibroblasts that reside in the compact myocardium. To form these epicardial-derived cells (EPDCs), the epicardium undergoes the process of epithelial to mesenchymal transition (EMT). Although several signaling pathways have been identified that disrupt EMT, no pathway has been reported that restricts this developmental process. Here, we identify neurofibromin 1 (Nf1) as a key mediator of epicardial EMT. To determine the function of Nf1 during epicardial EMT and the formation of epicardial derivatives, cardiac fibroblasts and cVSMCs, we generated mice with a tissue-specific deletion of Nf1 in the epicardium. We found that mutant epicardial cells transitioned more readily to mesenchymal cells in vitro and in vivo. The mesothelial epicardium lost epithelial gene expression and became more invasive. Using lineage tracing of EPDCs, we found that the process of EMT occurred earlier in Nf1 mutant hearts, with an increase in epicardial cells entering the compact myocardium. Moreover, loss of Nf1 caused increased EPDC proliferation and resulted in more cardiac fibroblasts and cVSMCs. Finally, we were able to partially reverse the excessive EMT caused by loss of Nf1 by disrupting Pdgfrα expression in the epicardium. Conversely, Nf1 activation was able to inhibit PDGF-induced epicardial EMT. Our results demonstrate a regulatory role for Nf1 during epicardial EMT and provide insights into the susceptibility of patients with disrupted NF1 signaling to cardiovascular disease.

show abstract

Section: Epicardial Inactivation Of Nf1 Results In Aberrant Epicardiumentioning

confidence: 99%

Section: Nf1 Regulation Of Ras Signaling Plays a Role In Pdgf-inducedmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Nf1 limits epicardial derivative expansion by regulating epithelial to mesenchymal transition and proliferation

Baek

Tallquist

2012

Development

View full text Add to dashboard Cite

show abstract

“…High Adm mRNA level has been associated with hypertension (50) and myocyte hypertrophy (51,52). NF1 patients frequently experience hypertension (53,54), and in the Nf1 knockout mouse model, Xu and colleagues reported that cardiomyocyte-specific knockdown of Nf1 contributed to the cardiac hypertrophy (55). In DS-5, Adm mRNA increased in ST88-14 but was downregulated by siNRas, and these alterations in gene expression could serve as the mechanistic basis for an NF1-related cardiovascular disease study.…”

Section: Discussionmentioning

confidence: 99%

RAS/MEK–Independent Gene Expression Reveals BMP2-Related Malignant Phenotypes in the Nf1-Deficient MPNST

Sun

Haddad

Kraniak

et al. 2013

Molecular Cancer Research

View full text Add to dashboard Cite

Malignant peripheral nerve sheath tumor (MPNST) is a type of soft tissue sarcoma that occurs in carriers of germline mutations in Nf1 gene as well as sporadically. Neurofibromin, encoded by the Nf1 gene, functions as a GTPase-activating protein (GAP) whose mutation leads to activation of wt-RAS and mitogen-activated protein kinase (MAPK) signaling in neurofibromatosis type I (NF1) patients' tumors. However, therapeutic targeting of RAS and MAPK have had limited success in this disease. In this study, we modulated NRAS, mitogen-activated protein/extracellular signal-regulated kinase (MEK)1/2, and neurofibromin levels in MPNST cells and determined gene expression changes to evaluate the regulation of signaling pathways in MPNST cells. Gene expression changes due to neurofibromin modulation but independent of NRAS and MEK1/2 regulation in MPNST cells indicated bone morphogenetic protein 2 (Bmp2) signaling as a key pathway. The BMP2-SMAD1/5/8 pathway was activated in NF1-associated MPNST cells and inhibition of BMP2 signaling by LDN-193189 or short hairpin RNA (shRNA) to BMP2 decreased the motility and invasion of NF1-associated MPNST cells. The pathway-specific gene changes provide a greater understanding of the complex role of neurofibromin in MPNST pathology and novel targets for drug discovery. Mol Cancer Res; 11(6); 616-27. Ó2013 AACR.

show abstract

“…Cardiac-specific Nf1-deleted mice develop marked cardiac hypertrophy, progressive cardiomyopathy, and fibrosis as adults (71).…”

Section: Figurementioning

confidence: 99%

MEK-ERK pathway modulation ameliorates disease phenotypes in a mouse model of Noonan syndrome associated with the Raf1L613V mutation

Simpson²,

Hong³

et al. 2011

J. Clin. Invest.

187

181

View full text Add to dashboard Cite

Hypertrophic cardiomyopathy (HCM) is a leading cause of sudden death in children and young adults. Abnormalities in several signaling pathways are implicated in the pathogenesis of HCM, but the role of the RAS-RAF-MEK-ERK MAPK pathway has been controversial. Noonan syndrome (NS) is one of several autosomal-dominant conditions known as RASopathies, which are caused by mutations in different components of this pathway. Germline mutations in RAF1 (which encodes the serine-threonine kinase RAF1) account for approximately 3%-5% of cases of NS. Unlike other NS alleles, RAF1 mutations that confer increased kinase activity are highly associated with HCM. To explore the pathogenesis of such mutations, we generated knockin mice expressing the NS-associated Raf1 L613V mutation. Like NS patients, mice heterozygous for this mutation (referred to herein as L613V/+ mice) had short stature, craniofacial dysmorphia, and hematologic abnormalities. Valvuloseptal development was normal, but L613V/+ mice exhibited eccentric cardiac hypertrophy and aberrant cardiac fetal gene expression, and decompensated following pressure overload. Agonist-evoked MEK-ERK activation was enhanced in multiple cell types, and postnatal MEK inhibition normalized the growth, facial, and cardiac defects in L613V/+ mice. These data show that different NS genes have intrinsically distinct pathological effects, demonstrate that enhanced MEK-ERK activity is critical for causing HCM and other RAF1-mutant NS phenotypes, and suggest a mutation-specific approach to the treatment of RASopathies.

show abstract

Cardiomyocyte-Specific Loss of Neurofibromin Promotes Cardiac Hypertrophy and Dysfunction

Cited by 41 publications

References 42 publications

Nf1 limits epicardial derivative expansion by regulating epithelial to mesenchymal transition and proliferation

Nf1 limits epicardial derivative expansion by regulating epithelial to mesenchymal transition and proliferation

RAS/MEK–Independent Gene Expression Reveals BMP2-Related Malignant Phenotypes in the Nf1-Deficient MPNST

MEK-ERK pathway modulation ameliorates disease phenotypes in a mouse model of Noonan syndrome associated with the Raf1L613V mutation

Contact Info

Product

Resources

About