title: Dominant negative Ras attenuates pathological ventricular remodeling in pressure overload cardiac hypertrophy.
abstract: 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.
authors.affiliation: Cardiovascular Research Center, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Centro de Investigación Social Avanzada. Querétaro, Mexico; Cardiovascular Research Center, Massachusetts General Hospital, Charlestown, MA, USA; Laboratorio de Biología Molecular, Universidad Panamericana, Mexico; Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Mexico. Electronic address: manuel.ramos@cisav.org.
authors.forename: Manuel
authors.initials: M
authors.lastname: Ramos-Kuri
authors.affiliation: Cardiovascular Research Center, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Kleopatra
authors.initials: K
authors.lastname: Rapti
authors.affiliation: INSERM UMR-S 1180, LabEx LERMIT DHU TORINO, Châtenay-Malabry, France; Faculté de Pharmacie, Université Paris-Sud, Châtenay-Malabry, France.
authors.forename: Hind
authors.initials: H
authors.lastname: Mehel
authors.affiliation: Cardiovascular Research Center, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA.
authors.forename: Shihong
authors.initials: S
authors.lastname: Zhang
authors.affiliation: Department of Pediatrics, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, NY, USA.
authors.forename: Perundurai S
authors.initials: PS
authors.lastname: Dhandapany
authors.affiliation: Cardiovascular Research Center, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Cardiovascular Research Center, Massachusetts General Hospital, Charlestown, MA, USA.
authors.forename: Lifan
authors.initials: L
authors.lastname: Liang
authors.affiliation: Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Mexico.
authors.forename: Alejandro
authors.initials: A
authors.lastname: García-Carrancá
authors.affiliation: INSERM U770, Université Paris Sud, Le Kremlin-Bicêtre, France.
authors.forename: Regis
authors.initials: R
authors.lastname: Bobe
authors.affiliation: INSERM UMR-S 1180, LabEx LERMIT DHU TORINO, Châtenay-Malabry, France; Faculté de Pharmacie, Université Paris-Sud, Châtenay-Malabry, France.
authors.forename: Rodolphe
authors.initials: R
authors.lastname: Fischmeister
authors.affiliation: INSERM U955 and Département de Physiologie, Hôpital Henri Mondor, AP-HP, 94010, Créteil, Université Paris-Est Créteil (UPEC), France.
authors.forename: Serge
authors.initials: S
authors.lastname: Adnot
authors.affiliation: Cardiovascular Research Center, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Cardiovascular Research Center, Massachusetts General Hospital, Charlestown, MA, USA.
authors.forename: Djamel
authors.initials: D
authors.lastname: Lebeche
authors.affiliation: Cardiovascular Research Center, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Cardiovascular Research Center, Massachusetts General Hospital, Charlestown, MA, USA.
authors.forename: Roger J
authors.initials: RJ
authors.lastname: Hajjar
authors.affiliation: Cardiovascular Research Center, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; INSERM U955 and Département de Physiologie, Hôpital Henri Mondor, AP-HP, 94010, Créteil, Université Paris-Est Créteil (UPEC), France.
authors.forename: Larissa
authors.initials: L
authors.lastname: Lipskaia
authors.affiliation: Cardiovascular Research Center, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Cardiovascular Research Center, Massachusetts General Hospital, Charlestown, MA, USA.
authors.forename: Elie R
authors.initials: ER
authors.lastname: Chemaly
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D006332:Cardiomegaly / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D020125:Mutation, Missense; D009206:Myocardium / Q000201:enzymology* / Q000473:pathology; D032383:Myocytes, Cardiac / Q000201:enzymology* / Q000473:pathology; D016283:Proto-Oncogene Proteins p21(ras) / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012518:Sarcomeres / Q000201:enzymology / Q000235:genetics; D020257:Ventricular Remodeling
chemical_list: D016283:Proto-Oncogene Proteins p21(ras)
keywords: Cardiac hypertrophy; Heart failure; Pathological hypertrophy; Physiological hypertrophy; Ras inhibition; Ras oncogene