October 1, 2004Open Access

Cardiac-specific disruption of the c-raf-1 gene induces cardiac dysfunction and apoptosis

Q: What is the clinical evidence from this study?

Study design: Other. Population: Cardiac dysfunction and apoptosis (n=235). Intervention: Cardiac-specific disruption of the c-raf-1 gene vs. Control littermates (wild-type c-raf-1). Primary outcome: Fractional shortening at 10 weeks of age (p=<0.05).

Key Result

Cardiac-specific disruption of the c-raf-1 gene in mice significantly depressed cardiac contractility, reducing fractional shortening to 19.3% compared to 38.4% in controls (p<0.05).

PICO

Population

Mice with cardiac muscle-specific disruption of the c-raf-1 gene and control littermates evaluated for cardiac function and apoptosis up to 15 weeks of age.

Exposure / Comparator

Cardiac-specific disruption of the c-raf-1 gene vs Control littermates (wild-type c-raf-1)

Primary Outcome

Fractional shortening at 10 weeks of age, p=<0.05

Main Result

Absolute Event Rate: 19.3% vs 38.4%

p-value: p=<0.05

Limitations

Cannot exclude the possibility that ablation of one gene leads to alteration of the expression profile of unrelated or related genes.
Cannot exclude the role of the MEK/ERK pathway in cardiac development or hypertrophy, since MEK1/2 and ERK can be activated in Raf CKO hearts.

Abstract

The Raf/MEK/extracellular signal-regulated kinase (ERK) signaling pathway regulates diverse cellular processes such as proliferation, differentiation, and apoptosis and is implicated as an important contributor to the pathogenesis of cardiac hypertrophy and heart failure.To examine the in vivo role of Raf-1 in the heart, we generated cardiac muscle-specific Raf-1-knockout (Raf CKO) mice with Cre-loxP-mediated recombination.The mice demonstrated left ventricular systolic dysfunction and heart dilatation without cardiac hypertrophy or lethality.The Raf CKO mice showed a significant increase in the number of apoptotic cardiomyocytes.The expression level and activation of MEK1/2 or ERK showed no difference, but the kinase activity of apoptosis signal-regulating kinase 1 (ASK1), JNK, or p38 increased significantly compared with that in controls.The ablation of ASK1 rescued heart dysfunction and dilatation as well as cardiac fibrosis.These results indicate that Raf-1 promotes cardiomyocyte survival through a MEK/ERK-independent mechanism. ResultsGeneration of cardiac muscle-specific Raf-1 knockout mice.To obtain a cardiac muscle-specific knockout of the c-raf-1 gene, we used Cre-Nonstandard abbreviations used: ASK1, apoptosis signal-regulating kinase 1; CTL, control littermate of c-raf-1 flox/flox :-MHCCre(-) mice; ERK, extracellular signal-regulated kinase; FS, fractional shortening; LV, left ventricle/ventricular; -MHCCre, transgenic mice expressing Cre recombinase under the control of the -myosin heavy chain promoter; MKK, mitogen-activated protein kinase kinase; Raf CKO, cardiac muscle-specific Raf-1 knockout; RV, right ventricle.

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Cite This Study

Yamaguchi et al. (Fri,) conducted a other in Cardiac dysfunction and apoptosis (n=235). Cardiac-specific disruption of the c-raf-1 gene vs. Control littermates (wild-type c-raf-1) was evaluated on Fractional shortening at 10 weeks of age (p=<0.05). Cardiac-specific disruption of the c-raf-1 gene in mice significantly depressed cardiac contractility, reducing fractional shortening to 19.3% compared to 38.4% in controls (p<0.05).

synapsesocial.com/papers/6a20137377451c29e065c702 https://doi.org/https://doi.org/10.1172/jci20317