Signaling to Cardiac Hypertrophy: Insights from Human and Mouse RASopathies

Sala, Valentina; Gallo, Simona; Leo, Christian; Gatti, Stefano; Gelb, Bruce D.; Crepaldi, Tiziana

doi:10.2119/molmed.2011.00512

Cited by 43 publications

(47 citation statements)

References 133 publications

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“…Taken together with the genetic and biochemical data, the results provide compelling evidence that RAF1 mutations play a critical role in DCM. While the role of RAS/MAPK signaling in myocardial biology is well established 7,12 , this is the first demonstration that its alteration can contribute to isolated DCM in humans.…”

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confidence: 83%

“…Signaling through mitogen-activated protein kinases (MAPKs) plays crucial roles in myocardial biology 7 . Germ-line mutations in genes encoding RAS-MAPK pathway members lead to several overlapping developmental syndromes termed the RASopathies, which include a high prevalence of HCM 8-12 .…”

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confidence: 99%

“…RASopathy genes do not appear to play a significant causal role in non-syndromic HCM 13 . Based on mouse genetic models, altered activities of certain proteins relevant for signaling through MAPKs such as loss of SHP-2, RAF1 or increased p38 activation can induce DCM 7 . However, inherited abnormalities in RAS-MAPK signaling have not been previously implicated in human patients with DCM.…”

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confidence: 99%

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RAF1 mutations in childhood-onset dilated cardiomyopathy

et al. 2014

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Dilated cardiomyopathy (DCM) is a highly heterogeneous trait with sarcomeric gene mutations predominating. The cause of a significant percentage of DCM remains unknown and no gene-specific therapy is available. Based on resequencing with 513 DCM cases and 1,150 matched controls from various ethnically distinct cohorts, we discovered rare, functional RAF1 mutations in three of them (South India, North India and Japan). The prevalence of RAF1 mutations was ~9% in childhood-onset DCM cases in those three cohorts. Biochemical studies showed that DCM-associated RAF1 mutants had altered kinase activity, resulting in largely unaltered ERK activation but AKT that was hyperactivated in a BRAF-dependent manner. Constitutive expression of these mutants in zebrafish embryos resulted in a heart failure phenotype with AKT hyperactivation that was rescued by rapamycin treatment. These findings provide new mechanistic insights and potential therapeutic targets for RAF1-associated DCM and further expand the clinical spectrum of RAF1-related human disorders.

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confidence: 83%

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confidence: 99%

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RAF1 mutations in childhood-onset dilated cardiomyopathy

et al. 2014

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“…The most frequently identified genetic syndrome associated with HCM is Noonan Syndrome/Costello/LEOPARD/Cardiofaciocutaneous (CFC) syndrome [12]. These syndromes represents a group of closely-related conditions that involve defects in the RAS-MAP kinase signaling pathway and are often referred to as RASopathies [13] which affect signaling by the HRAS proto-oncogene.…”

Section: Syndromic Hcmmentioning

confidence: 99%

“…Implicated genes include PTPN11, RAF1, SOS1, HRAS, KRAS, BRAF, MEK1, MEK2, and RIT1. HCM has been described in individuals with mutations in PTPN11, RAF1, SOS1, HRAS, KRAS, BRAF, and RIT1 [12]. Each can be associated with significant cardiac hypertrophy which may present in infancy and can be quite severe.…”

Section: Syndromic Hcmmentioning

confidence: 99%

How to effectively utilize genetic testing in the care of children with cardiomyopathies

Russell

Roberts

Abrams

et al. 2015

Progress in Pediatric Cardiology

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Tropisetron restores normal expression of BAD, SIRT1, SIRT3, and SIRT7 in the rat pressure overload‐induced cardiac hypertrophy model

Karimollah

Hemmatpur

Safari

et al. 2023

J Biochem & Molecular Tox

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Tropisetron exerts a protective effect against cardiac complications, particularly cardiac hypertrophy. Oxidative stress and apoptosis are the main contributors to the pathogenesis of cardiac hypertrophy. Sirtuins, a family of histone deacetylases, are connected to cellular oxidative stress signaling and antioxidant defense. Sirtuins are also linked to apoptosis which is an important mechanism in the progression of cardiac hypertrophy to heart failure. Literature also suggests that tropisetron impedes apoptosis, partly mediated through an antioxidant mechanism. Therefore, we examined if tropisetron fights cardiac hypertrophy by adjusting sirtuin family proteins (Sirts) and components of mitochondrial death pathway, Bcl-associated X (BAX), Bcl-2-associated death promoter (BAD). Male Sprague-Dawley rats got divided into four groups, including control (Ctl), tropisetron (Trop), cardiac hypertrophy (Hyp), and hypertrophic rats under tropisetron treatment (Hyp + Trop). Pathological cardiac hypertrophy was induced by surgical abdominal aortic constriction (AAC). The increased expression of brain natriuretic peptide (BNP) in the Hyp group confirms the cardiac hypertrophy establishment. The mRNA levels of SIRT1, SIRT3, SIRT7, and BAD also upregulated in the hypertrophic group (p < 0.001). Postoperational administration of tropisetron for 3 weeks lowered the increased expression of BNP (p < 0.05) and BAD (p < 0.001), though the reduction of BAX expression was statistically insignificant (p > 0.05). Tropisetron treatment also restored the normal level of SIRT1/3/7 genes expression in the Hyp + Trop group (p < 0.05). Present findings suggest that tropisetron can suppress cardiomyocyte hypertrophy progression to heart failure by counteracting BNP, SIRT1, SIRT3, Sirt7, and BAD overexpressionmediated apoptosis in a rat model of cardiac hypertrophy.

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Signaling to Cardiac Hypertrophy: Insights from Human and Mouse RASopathies

Cited by 43 publications

References 133 publications

RAF1 mutations in childhood-onset dilated cardiomyopathy

RAF1 mutations in childhood-onset dilated cardiomyopathy

How to effectively utilize genetic testing in the care of children with cardiomyopathies

Tropisetron restores normal expression of BAD, SIRT1, SIRT3, and SIRT7 in the rat pressure overload‐induced cardiac hypertrophy model

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