Myocardial deletion of <i>Smad4 </i>using a novel α skeletal muscle actin Cre recombinase transgenic mouse causes misalignment of the cardiac outflow tract

Azhar, Mohamad; Wang, Peiyu; Frugier, Tony; Koishi, Kyoko; Deng, Chu‐Xia; Noakes, Peter G.; McLennan, Ian S.

doi:10.7150/ijbs.6.546

Cited by 24 publications

(18 citation statements)

References 54 publications

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“…DCP1A , is a SMAD4 interacting protein; SMAD4 is a downstream target of the BMP signaling pathway involved in cardiac development [75]. In mice, myocardial deletion of Smad4 has been shown to result in impaired trabeculation and thinning of ventricular myocardium [76]. …”

Section: Resultsmentioning

confidence: 99%

Genetic Variants in Isolated Ebstein Anomaly Implicated in Myocardial Development Pathways

et al. 2016

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Ebstein anomaly (EA) is a rare heart defect in which the tricuspid valve is malformed and displaced. The tricuspid valve abnormalities can lead to backflow of blood from the right ventricle to the right atrium, preventing proper circulation of blood to the lungs. Although the etiology of EA is largely unresolved, increased prevalence of EA in those with a family history of congenital heart disease suggests EA has a genetic component. Copy number variants (CNVs) are a major source of genetic variation and have been implicated in a range of congenital heart defect phenotypes. We performed a systematic, genome-wide search for CNVs in 47 isolated EA cases using genotyping microarrays. In addition, we used a custom HaloPlex panel to sequence three known EA genes and 47 candidate EA genes. We identified 35 candidate CNVs in 24 (51%) EA cases. Rare sequence variants in genes associated with cardiomyopathy were identified in 11 (23%) EA cases. Two CNVs near the transcriptional repressor HEY1, a member of the NOTCH signaling pathway, were identified in three unrelated cases. All other candidate CNVs were each identified in a single case. At least 11 of 35 candidate CNVs include genes involved in myocardial development or function, including multiple genes in the BMP signaling pathway. We identified enrichment of gene sets involved in histone modification and cardiomyocyte differentiation, supporting the involvement of the developing myocardium in the etiology of EA. Gene set enrichment analysis also identified ribosomal RNA processing, a potentially novel pathway of altered cardiac development in EA. Our results suggest an altered myocardial program may contribute to abnormal tricuspid valve development in EA. Future studies should investigate abnormal differentiation of cardiomyocytes as a potential etiological factor in EA.

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Section: Resultsmentioning

confidence: 99%

Genetic Variants in Isolated Ebstein Anomaly Implicated in Myocardial Development Pathways

et al. 2016

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“…Both control Nrf2 ϩ/ϩ and Nrf2 Ϫ/Ϫ mice were obtained from ICR background Nrf2 heterozygous mating pairs (8). MuCreA mice (19) were kindly supplied by the RIKEN BioResource Center (Tsukuba, Japan). Alb-Cre mice were supplied by Jackson Laboratory (Bar Harbor, ME).…”

Section: Mice Both Db/db::keap1mentioning

confidence: 99%

The Keap1-Nrf2 System Prevents Onset of Diabetes Mellitus

Uruno

Furusawa

Yagishita

et al. 2013

Molecular and Cellular Biology

284

260

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e Transcription factor Nrf2 (NF-E2-related factor 2) regulates a broad cytoprotective response to environmental stresses. Keap1 (Kelch-like ECH-associated protein 1) is an adaptor protein for cullin3-based ubiquitin E3 ligase and negatively regulates Nrf2. Whereas the Keap1-Nrf2 system plays important roles in oxidative stress response and metabolism, the roles Nrf2 plays in the prevention of diabetes mellitus remain elusive. Here we show that genetic activation of Nrf2 signaling by Keap1 gene hypomorphic knockdown (Keap1 flox/؊ ) markedly suppresses the onset of diabetes. When Keap1 flox/؊ mice were crossed with diabetic db/db mice, blood glucose levels became lower through improvement of both insulin secretion and insulin resistance. Keap1 flox/؊ also prevented high-calorie-diet-induced diabetes. Oral administration of the Nrf2 inducer CDDO-Im {oleanolic acid 1-[2-cyano-3,12-dioxooleana-1,9(11)-dien-28-oyl] imidazole} also attenuated diabetes in db/db mice. Nrf2 induction altered antioxidant-, energy consumption-, and gluconeogenesis-related gene expression in metabolic tissues. Thus, the Keap1-Nrf2 system is a critical target for preventing the onset of diabetes mellitus.

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“…Partial deletion of Smad4 (haploinsuffciency) results in premature death caused by the worsening of aortic aneurysm and rupture in mouse of model of Marfan syndrome (Holm et al 2011). In addition, Smad4 plays important roles in valves and myocardium during cardiac development (Azhar et al 2010;Nie et al 2008;Moskowitz et al 2011). Furthermore, conditional loss of Smad4 in myocardium can cause spontaneous cardiac hypertrophy (Song et al 2007).…”

Section: Tgfβ Effector Molecules In Cardiovascular Diseasesmentioning

confidence: 99%

“…Since SMAD4 is co-SMAD molecule for both TGFβ and BMP signaling, the direct role of TGFβ signaling in the regulation of JNK1 signaling in the Marfan mouse model remains unclear. Similarly, strategies that would target SMAD4 may also be detrimental for overall health since conditional tissue-specific deletion of Smad4 has revealed its important role in cardiac development and cardiac hypertrophy, and cancer (Azhar et al 2010;Nie et al 2008;Yang and Yang 2010;Wang et al 2005) (Song et al 2011;Kim et al 2006). Collectively, the concerns about the undesirable outcome of non-specific targeting of TGFβ pathway molecules may be valid, and a better knowledge of the function of TGFβ ligands, receptors and effectors in the adult cardiovascular system is an essential prerequisite before embarking on any TGFβ-based therapy to treat cardiovascular diseases.…”

Section: Tgfβ-based Therapies and Its Potential Complications For Carmentioning

confidence: 99%

Transforming growth factor beta signaling in adult cardiovascular diseases and repair

et al. 2011

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The majority of children with congenital heart disease now live into adulthood due to the remarkable surgical and medical advances that have taken place over the past half century. Because of this, the adults now represent the largest age group with adult cardiovascular diseases. They include patients with heart diseases that were not detected or not treated during childhood, those whose defects were surgically corrected but now need revision due to maladaptive responses to the procedure, those with exercise problems, and those with age-related degenerative diseases. Because adult cardiovascular diseases in this population are relatively new, they are not well understood. It is therefore necessary to understand the molecular and physiological pathways involved if we are to improve treatments. Since there is a developmental basis to adult cardiovascular disease, transforming growth factor beta (TGFβ) signaling pathways that are essential for proper cardiovascular development may also play critical roles in the homeostatic, repair and stress response processes involved in adult cardiovascular diseases. Consequently, we have chosen to summarize the current information on a subset of TGFβ ligand and receptor genes and related effector genes that when dysregulated are known to lead to cardiovascular diseases and adult cardiovascular deficiencies and/or pathologies. A better understanding of the TGFβ signaling network in cardiovascular disease and repair will impact genetic and physiologic investigations of cardiovascular diseases in elderly patients and lead to an improvement in clinical interventions.

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Myocardial deletion of Smad4 using a novel α skeletal muscle actin Cre recombinase transgenic mouse causes misalignment of the cardiac outflow tract

Cited by 24 publications

References 54 publications

Genetic Variants in Isolated Ebstein Anomaly Implicated in Myocardial Development Pathways

Genetic Variants in Isolated Ebstein Anomaly Implicated in Myocardial Development Pathways

The Keap1-Nrf2 System Prevents Onset of Diabetes Mellitus

Transforming growth factor beta signaling in adult cardiovascular diseases and repair

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