Dominant negative Ras attenuates pathological ventricular remodeling in pressure overload cardiac hypertrophy
Por:
Ramos-Kuri M., Rapti K., Mehel H., Zhang S., Dhandapany P.S., Liang L., García-Carrancá A., Bobe R., Fischmeister R., Adnot S., Lebeche D., Hajjar R.J., Lipskaia L., Chemaly E.R.
Publicada:
1 nov 2015
Resumen:
The importance of the oncogene Ras in cardiac hypertrophy is well appreciated. The hypertrophic 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-hypertrophic effect of Ras inhibition in vitro using rat neonatal cardiomyocytes (NRCM) and in vivo in the setting of pressure-overload left ventricular (LV) hypertrophy (POH) in rats. 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 NFAT resulting in pro-hypertrophic and cardio-toxic effects on NRCM beating and Z-line organization. In contrast, the DN-Ras was antihypertrophic on NRCM, inhibited NFAT and exerted cardio-protective effects attested by preserved NRCM beating and Z line structure. Additional experiments with silencing H-Ras gene strategy corroborated the antihypertrophic effects of siRNA-H-Ras on NRCM. In vivo, with the POH model, both Ras mutants were associated with similar hypertrophy two weeks after simultaneous induction of POH 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 cardiac hypertrophy. In isolated adult cardiomyocytes after 2. weeks of POH and Ras-mutant gene transfer, DN-Ras improved sarcomere shortening and calcium transients compared to Ras-Val12. Overall, DN-Ras promotes a more physiological form of hypertrophy, suggesting an interesting therapeutic target for pathological cardiac hypertrophy. © 2015 Elsevier B.V.
Filiaciones:
Ramos-Kuri M.:
Univ Nacl Autonoma Mexico, Inst Invest Biomed, Mexico City 04510, DF, Mexico
Rapti K.:
Cardiovascular Research Center, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States
Mehel H.:
INSERM UMR-S 1180, LabEx LERMIT DHU TORINO, Châtenay-Malabry, France
Faculté de Pharmacie, Université Paris-Sud, Châtenay-Malabry, France
Zhang S.:
Cardiovascular Research Center, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States
Dhandapany P.S.:
Department of Pediatrics, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy PlaceNY, United States
Liang L.:
Cardiovascular Research Center, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States
Cardiovascular Research Center, Massachusetts General Hospital, Charlestown, MA, United States
García-Carrancá A.:
Univ Nacl Autonoma Mexico, Inst Invest Biomed, Mexico City 04510, DF, Mexico
Bobe R.:
INSERM U770, Université Paris Sud, Le Kremlin-Bicêtre, France
Fischmeister R.:
INSERM UMR-S 1180, LabEx LERMIT DHU TORINO, Châtenay-Malabry, France
Faculté de Pharmacie, Université Paris-Sud, Châtenay-Malabry, France
Adnot S.:
INSERM U955 and Département de Physiologie, Hôpital Henri Mondor, Université Paris-Est Créteil (UPEC), AP-HP, Créteil, 94010, France
Lebeche D.:
Cardiovascular Research Center, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States
Cardiovascular Research Center, Massachusetts General Hospital, Charlestown, MA, United States
Hajjar R.J.:
Cardiovascular Research Center, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States
Cardiovascular Research Center, Massachusetts General Hospital, Charlestown, MA, United States
Lipskaia L.:
Cardiovascular Research Center, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States
INSERM U955 and Département de Physiologie, Hôpital Henri Mondor, Université Paris-Est Créteil (UPEC), AP-HP, Créteil, 94010, France
Chemaly E.R.:
Cardiovascular Research Center, Icahn School of Medicine at Mount Sinai, New York, NY 10029, United States
Cardiovascular Research Center, Massachusetts General Hospital, Charlestown, MA, United States
All Open Access, Bronze
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