HRas-dependent pathways can activate morphological and genetic markers of cardiac muscle cell hypertrophy.

Thorburn, Andrew; Thorburn, Jacqueline; Chen, Sei-Yu; Powers, Scott; Shubeita, Huda E.; Feramisco, James R.; Chien, Kenneth R.

doi:10.1016/s0021-9258(18)53988-0

Cited by 203 publications

(12 citation statements)

References 26 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Importantly, more than 50% of patients with Noonan syndrome display a pathogenic mutation in the PTPN11 gene encoding SHP-2 protein [7]. In line with this, Thorburn et al [5] reported that, in cardiomyocytes, the active mutant of Src-F527 activated H-Ras and induced cardiac hypertrophy.…”

Section: Ras Adaptor Proteinsmentioning

confidence: 88%

“…As previously mentioned, pioneering studies of oncogenes in cardiomyocytes in vitro showed that oncogenic H-Ras induced hypertrophy [ 5 ]. In contrast to the effects of such mutants on other cell lineages, they did not activate malignant transformation of cardiomyocytes, but instead induced cardiac hypertrophy the with expression of classical markers of pathological hypertrophy such as Atrial Natriuretic Factor (ANF), Skeletal Muscle α Actin (SkM-α Actin), β-Myosin Heavy Chain (β-MHC) and c-Fos in neonatal cardiomyocytes in vitro [ 5 , 14 , 15 ].…”

Section: Role Of H- K- and N Ras In Cardiac Hypertrophymentioning

confidence: 99%

“…The effect of Ras-Val12 on the sarcomeric structure of neonatal cardiomyocytes in vitro has been controversial, since two independent studies reported that Ras-Val12 induced hypertrophy with enhanced or unchanged sarcomeric organization [ 5 , 27 ], while other in vitro studies showed that Ras-Val12 caused myofibrillar disorganization [ 25 ], or reduced myofibrillar density [ 28 ]. Also, in transgenic mice, the active mutant H-Ras-Val12 caused obstructive hypertrophy with myofibrillar disarray, similar to hypertrophic cardiomyopathy (HCM) [ 29 , 30 ], or severe hypertrophy with diastolic dysfunction [ 27 , 30 ].…”

Section: Role Of H- K- and N Ras In Cardiac Hypertrophymentioning

confidence: 99%

“…These genes are proto-oncogenes, and their mutated versions are responsible for neoplastic transformation; they are the most frequently mutated genes in all cancer types [3,4]. In 1993, Thorburn et al showed that H-Ras-Val12, an oncogenic mutant of H-Ras, induced hypertrophy of rat neonatal cardiomyocytes in vitro without oncogenic transformation [5]. The role of intracellular pathways involving small G proteins, including Ras, Rho and Rac, in cardiac hypertrophy is well established, as detailed in previous reviews [1,2,[6][7][8][9].…”

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Molecules linked to Ras signaling as therapeutic targets in cardiac pathologies

et al. 2021

View full text Add to dashboard Cite

The Ras family of small Guanosine Triphosphate (GTP)-binding proteins (G proteins) represents one of the main components of intracellular signal transduction required for normal cardiac growth, but is also critically involved in the development of cardiac hypertrophy and heart failure. The present review provides an update on the role of the H-, K- and N-Ras genes and their related pathways in cardiac diseases. We focus on cardiac hypertrophy and heart failure, where Ras has been studied the most. We also review other cardiac diseases, like genetic disorders related to Ras. The scope of the review extends from fundamental concepts to therapeutic applications. Although the three Ras genes have a nearly identical primary structure, there are important functional differences between them: H-Ras mainly regulates cardiomyocyte size, whereas K-Ras regulates cardiomyocyte proliferation. N-Ras is the least studied in cardiac cells and is less associated to cardiac defects. Clinically, oncogenic H-Ras causes Costello syndrome and facio-cutaneous-skeletal syndromes with hypertrophic cardiomyopathy and arrhythmias. On the other hand, oncogenic K-Ras and alterations of other genes of the Ras-Mitogen-Activated Protein Kinase (MAPK) pathway, like Raf, cause Noonan syndrome and cardio-facio-cutaneous syndromes characterized by cardiac hypertrophy and septal defects. We further review the modulation by Ras of key signaling pathways in the cardiomyocyte, including: (i) the classical Ras-Raf-MAPK pathway, which leads to a more physiological form of cardiac hypertrophy; as well as other pathways associated with pathological cardiac hypertrophy, like (ii) The SAPK (stress activated protein kinase) pathways p38 and JNK; and (iii) The alternative pathway Raf-Calcineurin-Nuclear Factor of Activated T cells (NFAT). Genetic alterations of Ras isoforms or of genes in the Ras-MAPK pathway result in Ras-opathies, conditions frequently associated with cardiac hypertrophy or septal defects among other cardiac diseases. Several studies underline the potential role of H- and K-Ras as a hinge between physiological and pathological cardiac hypertrophy, and as potential therapeutic targets in cardiac hypertrophy and failure. Graphic abstract

show abstract

Section: Ras Adaptor Proteinsmentioning

confidence: 88%

Section: Role Of H- K- and N Ras In Cardiac Hypertrophymentioning

confidence: 99%

Section: Role Of H- K- and N Ras In Cardiac Hypertrophymentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Molecules linked to Ras signaling as therapeutic targets in cardiac pathologies

et al. 2021

View full text Add to dashboard Cite

show abstract

“…The rat sarcoma (RAS) protein exists in cardiac myocytes as well as in cancer cells, and its high level of expression relates to numerous growth responses, such as promotion of cardiac hypertrophy, and is an important risk factor for CHF (56). HRAS, an isoform of Ras proteins, can regulate the PI3K-AKT signaling pathway and may be an important modulator of cardiac growth (57,58). It has been reported that the expression of the MAPK1 [also known as extracellular regulated protein kinase 2 (ERK2)] gene and protein increases rapidly in CHF rats, and the process of cardiac remodeling is delayed by inhibiting the expression of ERK2 (59).…”

Section: Discussionmentioning

confidence: 99%

Integration of network pharmacology and molecular docking technology reveals the mechanism of the herbal pairing of Codonopsis Pilosula (Franch.) Nannf and Astragalus Membranaceus (Fisch.) Bge on chronic heart failure

Zhang

Zhou

et al. 2021

Ann Palliat Med

View full text Add to dashboard Cite

Background: The herbal pairing of Dangshen (DS) [Codonopsis pilosula (Franch.) Nannf.] and Huangqi (HQ) [Astragalus membranaceus (Fisch.) Bge.] (DHP) is a traditional Chinese herbal medicine that is frequently used to treat chronic heart failure (CHF) in China. However, the pharmacological mechanism of DHP has not been fully elucidated. This is the first study aimed to reveal the active mechanism of DHP in the treatment of CHF by using network pharmacology methods. Methods:The active ingredients of DHP were obtained from the TCMSP database, and the potential targets of DHP were predicted using the SwissTargetPrediction database. CHF-related targets were searched by the DisGeNET and GeneCards databases. The common targets between the disease and herbs were obtained using a Venn diagram. The STRING database was utilized to obtain the protein-protein interaction data. Next, we used Cytoscape 3.7.2 software to construct and analyze the herb-ingredientpotential targets-disease network. Topology analysis was used to identify the key ingredients and hub genes.GO and KEGG pathway enrichment analyses were performed using the Metascape database to reveal the mechanism. Furthermore, molecular docking simulation was performed using AutoDock Vina software to assess the affinity of the key ingredients and hub genes.Results: Five key ingredients and six hub genes were screened. The six hub genes were closely related to PI3K /AKT or ERK1/2 pathways. The KEGG pathways mainly involved the TNF signaling pathway, calcium signaling pathway, and cancer-related pathways. The GO enrichment analysis results showed that DHP might act on biological processes including positive regulation of kinase activity and cellular response to nitrogen compound via the three above-mentioned pathways in the treatment of CHF. Finally, the molecular docking results showed that the five key ingredients exhibited strong affinities to the six hub genes.Conclusions: This study revealed the molecular mechanism that the flavonoids in DHP may alleviate endothelial dysfunction and cardiac hypertrophy via regulation of the TNF pathway and its downstream PI3K/Akt or ERK1/2 signaling pathways, or improve excitation-contraction coupling by regulating calcium ^ ORCID: Jianglin Xu,

show abstract

Differential expression of c-jun and junD in end-stage human cardiomyopathy

et al. 1997

View full text Add to dashboard Cite

The proto-oncogenes c-jun and junD are closely related transcriptional factors with opposing actions on cell growth and division. Expression of c-jun rapidly increases as cells enter the cell cycle. Levels of c-jun are also increased in the early stages of experimental cardiac hypertrophy and failure but expression decreases with time. In contrast, junD accumulates in quiescent cells. Expression in end-stage cardiomyopathy has not been studied. Steady-state levels of c-jun and junD mRNA were determined in failing human myocardium (obtained at the time of cardiac transplantation) and in control myocardium from patients who died of noncardiac causes. Relative expression was normalized for glyceraldehyde-3-phosphate dehydrogenase expression. Levels of junD were almost four-fold depressed in myocardium from myopathic hearts (2.1 +/- 0.27, x +/- SE; n = 20) vs. the controls (7.7 +/- 1.1; n = 3). Levels of c-jun were similar in both myopathic and control hearts. Relative expression of beta-myosin heavy chain was the same in both myopathic and control hearts. Levels of junD were still found to be depressed in the myopathic hearts after normalization for myosin heavy chain gene expression. We conclude that c-jun and junD are differentially regulated in end-stage human cardiomyopathy with expression of junD being decreased while relative levels of c-jun mRNA remain unchanged. Further studies are needed to determine the role of junD down-regulation in the development and/or maintenance of the abnormalities present in end-stage heart disease.

show abstract

HRas-dependent pathways can activate morphological and genetic markers of cardiac muscle cell hypertrophy.

Cited by 203 publications

References 26 publications

Molecules linked to Ras signaling as therapeutic targets in cardiac pathologies

Molecules linked to Ras signaling as therapeutic targets in cardiac pathologies

Integration of network pharmacology and molecular docking technology reveals the mechanism of the herbal pairing of Codonopsis Pilosula (Franch.) Nannf and Astragalus Membranaceus (Fisch.) Bge on chronic heart failure

Differential expression of c-jun and junD in end-stage human cardiomyopathy

Contact Info

Product

Resources

About