Table 1 Summary of H, K and N-Ras mutants with gain or loss of function, in vitro (cardiomyocytes in culture) and in vivo (rodent models and clinical syndromes)
From: Molecules linked to Ras signaling as therapeutic targets in cardiac pathologies
| Increased function | Decreased function | |
|---|---|---|
| H-Ras |
In vitro: Ras Val12 [25, 28]: Hypertrophy with sarcomeric disruption Inhibition of cardiomyocyte beating In vivo: Ras Val12 in mice [12, 41]: Hypertrophic cardiomyopathy H-Ras wild type compensates K-Ras−/− in mice Clinical: Costello syndrome [81] Hypertrophic cardiomyopathy Arrhythmias |
In vitro: DN-Ras [25]: Enhancement of cardiomyocyte beating Enhancement of sarcomeric structure In vivo: experiments of H-Ras inhibition [25, 33]: DN-Ras favors physiological cardiac hypertrophy in a rat model of pressure overload Potential therapy for pathological cardiac hypertrophy and heart failure H-Ras−/− mice: normal heart and offsprings Clinical: no data |
| K-Ras |
In vitro: Active K-Ras V14I in cardiomyocyte [34]: Increased mitosis In vivo: K-Ras V14I mice [34]: Hyperplasia with no hypertrophy Clinical: Noonan or cardio-facio-cutaneous syndromes [80]: Hypertrophic cardiomyopathy Atrial and ventricular septal defects Pulmonary valve stenosis |
In vitro: No data In vivo: K-Ras−/− mice [33, 35]: Very low proliferation of cardiomyocytes, lethal at embryonic day 15.5 with extremely thin ventricular walls K-Ras is the only essential gene in the Ras subfamily K-Ras ± mice: normal at birth and protected in pressure overload Clinical: no data |
| N-Ras |
In vitro: No data on cardiac cells In vivo: N-Ras G12D mice [110] Mutated mouse embryos with cardiac malformations mimicking Noonan Syndrome: ventricular septal defects, double outlet right ventricle, hypertrabeculated/thin myocardium and pulmonic valve stenosis Clinical: Noonan syndrome—some cases [37] |
In vitro: No data In vivo: N-Ras−−/− mice [33]: Normal heart, normal offsprings Clinical: no data |