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Dominant negative Ras attenuates pathological ventricular remodeling in pressure overload cardiac hypertrophy
Manuel Ramos-Kuri1, Kleopatra Rapti2, Hind Mehel3
1Cardiovascular 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.
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.
Insights
Inhibition of the Ras oncogene may offer a therapeutic strategy for pathological cardiac hypertrophy. Dominant-negative Ras (DN-Ras) demonstrated anti-hypertrophic and cardio-protective effects in both cell and animal models.
Area of Science:
- Cardiology
- Molecular Biology
- Oncology
Background:
- The oncogene Ras plays a significant role in cardiac hypertrophy.
- Constitutively active Ras-Val12 mutations are linked to clinical syndromes and experimental evidence of cardiac hypertrophy.
- Understanding Ras signaling is crucial for developing therapeutic interventions for heart conditions.
Purpose of the Study:
- To investigate the potential anti-hypertrophic effects of Ras inhibition.
- To evaluate the impact of dominant-negative Ras (DN-Ras) on cardiac hypertrophy in vitro and in vivo.
- To explore Ras signaling as a therapeutic target for pathological cardiac hypertrophy.
Main Methods:
- Utilized adenovirus-directed gene transfer to modulate Ras function with Ras-Val12 and dominant-negative Ras (DN-Ras) in rat neonatal cardiomyocytes (NRCM) and a pressure-overload left ventricular (LV) hypertrophy (POH) rat model.
- Assessed NRCM beating, Z-line organization, and NFAT activation in vitro.
- Analyzed LV diameters, LV fractional shortening, cardiomyocyte cross-sectional area, and markers of pathological cardiac hypertrophy in vivo.
- Evaluated sarcomere shortening and calcium transients in isolated adult cardiomyocytes.
Main Results:
- Ras-Val12 expression induced pro-hypertrophic and cardio-toxic effects in NRCM by activating NFAT.
- DN-Ras exhibited anti-hypertrophic and cardio-protective effects in NRCM, inhibiting NFAT and preserving cellular structure.
- In vivo POH models showed that DN-Ras reduced cardiomyocyte size and pathological hypertrophy markers.
- DN-Ras improved cardiomyocyte function in adult cardiomyocytes subjected to POH.
Conclusions:
- Dominant-negative Ras (DN-Ras) demonstrates significant anti-hypertrophic and cardio-protective properties.
- DN-Ras promotes a more physiological form of cardiac hypertrophy, contrasting with the detrimental effects of Ras-Val12.
- Ras inhibition, particularly via DN-Ras, represents a promising therapeutic avenue for pathological cardiac hypertrophy.
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