Journal
JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY
Volume 41, Issue 4, Pages 613-622Publisher
ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD
DOI: 10.1016/j.yjmcc.2006.05.009
Keywords
reactive oxygen species; hypertrophy; strain; cardiac myocyte; Ras; Erk1/2; glutathiolation; glutaredoxin; catalase
Categories
Funding
- NCI NIH HHS [CA95191, CA96989] Funding Source: Medline
- NHLBI NIH HHS [HL55620, HL61639, N01-HV-28178, HL07224, HL007969, HL20612] Funding Source: Medline
- NIA NIH HHS [AG27080] Funding Source: Medline
Ask authors/readers for more resources
Although reactive oxygen species (ROS) appear to play a central role in mediating myocardial hypertrophy in response to hemodynamic overload, little is known about the molecular targets by which ROS regulate growth signaling. In cardiac myocytes, we tested the hypothesis that mechanical strain causes cellular hypertrophy via ROS-dependent post-translational modification of Ras leading to activation of the Raf/Mek/Erk growth pathway. Cyclic mechanical strain increased Ras activity by 1.5 to 1.6-fold. Adenoviral overexpression of the N17 dominant, negative mutant of Ras inhibited strain-stimulated Erk activation and protein synthesis. Strain-stimulated Ras activation was inhibited by overexpression of catalase, indicating that it is redox-dependent. Strain caused S-glutathiolation of Ras, which was inhibited by catalase overexpression and reversed by DTT. MALDI-TOF mass spectrometry demonstrated that in myocytes subjected to strain there was S-glutathiolation of Ras at Cys118. Adenoviral overexpression of a mutated Ras in which Cys118 was substituted with serine inhibited strain-stimulated S-glutathiolation of Ras, Erk activation and protein synthesis. Overexpression of glutaredoxin-1 likewise inhibited strain-stimulated Ras S-glutathiolation, Ras activation, Erk activation and protein synthesis. These findings indicate that mechanical strain causes ROS-dependent S-glutathiolation of Ras at Cys118, leading to myocyte hypertrophy via activation of the Raf/Mek/Erk pathway. (c) 2006 Elsevier Inc. All rights reserved.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available