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Progression to Heart Failure Modulated in a Conditional H‐Ras‐V12 Mouse Model of Human Cardiomyopathy
Author(s) -
Spehalski Elizabeth,
Martin Philip L,
Rozenberg Julian M,
Hoenerhoff Mark J,
Hoover Shelley B,
Walling Brent E,
Vinson Charles R,
Simpson R M
Publication year - 2007
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.21.5.a129
Subject(s) - hras , heart failure , mapk/erk pathway , weaning , cardiomyopathy , medicine , muscle hypertrophy , endocrinology , biology , signal transduction , microbiology and biotechnology , cancer , colorectal cancer , kras
Some cardiomyopathies (CM) are associated with altered Ras‐MAPK pathway signaling. A doxycycline conditional transgenic mouse model of HRas‐V12 expression was examined for effects of discontinuing Ras expression after onset of CM. 8 weeks of Ras expression initiated at weaning resulted in morbidity due to congestive heart failure (CHF) in 9/21 (43%) mice. CHF was detectable by echocardiography. Affected hearts had myofiber hypertrophy and degeneration similar to human CM, and up‐regulation of specific genes associated with CM. 4 weeks Ras expression followed by 4 weeks Ras inactivation resulted in 3/27 (11%) mice with CHF, indicating a survival benefit. Hypertrophic myofibers expressed Ras and pERK and labeled with periodic acid Schiff's reagent (PAS). Interspersed morphologically normal myofibers were typically unlabeled by any of these markers. There were fewer Ras, pERK and PAS labeled cardiomyofibers in mice with 2 weeks of Ras expression followed by inactivation of Ras for 1 week compared to mice with continuous Ras activation. Ras / ERK expression were minimal 4 weeks after inactivation in a similar cohort; correlating with reduced lesion severity (p>0.01). Ras expression was heterogeneous, leading to CM lesions that occurred as early as 2 weeks post weaning, and were modulated by removing the Ras‐MAPK stimulating effect, preventing progression to CHF. Supported by the NIH intramural research program.