Dominant negative Ras attenuates pathological ventricular remodeling in pressure overload XXXX .

@entity1184 @entity1283 @entity460 @entity28630 @entity35 @entity3803 @entity9980
The importance of the oncogene Ras in @entity1283 is well appreciated. The @entity1184 effects of the constitutively active mutant Ras-Val12 are revealed by clinical syndromes due to the Ras mutations and experimental studies. We examined the possible anti- @entity1184 effect of Ras inhibition in vitro using @entity35 neonatal cardiomyocytes (NRCM) and in vivo in the setting of pressure-overload left ventricular (LV) @entity1184 ( @entity9980 ) in @entity35 . Ras functions were modulated via adenovirus directed gene transfer of active mutant Ras-Val12 or dominant negative mutant N17-DN-Ras (DN-Ras). Ras-Val12 expression in vitro activates @entity28630 resulting in pro- @entity1184 and cardio-toxic effects on NRCM beating and Z-line organization. In contrast, the DN-Ras was antihypertrophic on NRCM, inhibited @entity28630 and exerted cardio-protective effects attested by preserved NRCM beating and Z line structure. Additional experiments with silencing @entity3803 gene strategy corroborated the antihypertrophic effects of siRNA- @entity3803 on NRCM. In vivo, with the @entity9980 model, both Ras mutants were associated with similar @entity1184 two weeks after simultaneous induction of @entity9980 and Ras-mutant gene transfer. However, LV diameters were higher and LV fractional shortening lower in the Ras-Val12 group compared to control and DN-Ras. Moreover, DN-Ras reduced the cross-sectional area of cardiomyocytes in vivo, and decreased the expression of markers of pathologic @entity1283 . In isolated adult cardiomyocytes after 2 weeks of @entity9980 and Ras-mutant gene transfer, DN-Ras improved sarcomere shortening and @entity460 transients compared to Ras-Val12. Overall, DN-Ras promotes a more physiological form of @entity1184 , suggesting an interesting therapeutic target for pathological @entity1283 .
