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Proapoptotic Rassf1A/Mst1 signaling in cardiac fibroblasts is protective against pressure overload in mice
Dominic P. Del Re, … , Louise Van Der Weyden, Junichi Sadoshima
Dominic P. Del Re, … , Louise Van Der Weyden, Junichi Sadoshima
Published September 20, 2010
Citation Information: J Clin Invest. 2010;120(10):3555-3567. https://doi.org/10.1172/JCI43569.
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Research Article Cardiology

Proapoptotic Rassf1A/Mst1 signaling in cardiac fibroblasts is protective against pressure overload in mice

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Abstract

Mammalian sterile 20-like kinase 1 (Mst1) is a mammalian homolog of Drosophila Hippo, the master regulator of cell death, proliferation, and organ size in flies. It is the chief component of the mammalian Hippo pathway and promotes apoptosis and inhibits compensatory cardiac hypertrophy, playing a critical role in mediating heart failure. How Mst1 is regulated, however, remains unclear. Using genetically altered mice in which expression of the tumor suppressor Ras-association domain family 1 isoform A (Rassf1A) was modulated in a cell type–specific manner, we demonstrate here that Rassf1A is an endogenous activator of Mst1 in the heart. Although the Rassf1A/Mst1 pathway promoted apoptosis in cardiomyocytes, thereby playing a detrimental role, the same pathway surprisingly inhibited fibroblast proliferation and cardiac hypertrophy through both cell-autonomous and autocrine/paracrine mechanisms, playing a protective role during pressure overload. In cardiac fibroblasts, the Rassf1A/Mst1 pathway negatively regulated TNF-α, a key mediator of hypertrophy, fibrosis, and resulting cardiac dysfunction. These results suggest that the functional consequence of activating the proapoptotic Rassf1A/Mst1 pathway during pressure overload is cell type dependent in the heart and that suppressing this mechanism in cardiac fibroblasts could be detrimental.

Authors

Dominic P. Del Re, Takahisa Matsuda, Peiyong Zhai, Shumin Gao, Geoffrey J. Clark, Louise Van Der Weyden, Junichi Sadoshima

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Figure 3

Systemic ablation of rassf1A causes exaggerated stress-induced hypertrophy and fibrosis in the heart.

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Systemic ablation of rassf1A causes exaggerated stress-induced hypertrop...
TAC was performed to generate pressure overload in vivo for 1 week. (A) Representative immunoblot demonstrated abolished Mst1 phosphorylation in rassf1A systemic KO versus WT hearts. (B) Quantification of immunoblot results (n = 3). Values are relative to sham-operated WT. (C) LVW/TL demonstrated increased cardiac hypertrophy in KO mice after TAC. (D) Cardiomyocyte cross-sectional area (shown relative to sham-operated WT) showed increased myocyte area in KO hearts after TAC. (E) Wheat germ agglutinin–stained representative images. (F) Fibrosis was assessed by Masson trichrome staining and fibrotic area determined. (G) Representative images showing exaggerated fibrosis in KO versus WT hearts. (H) Decreased cardiomyocyte apoptosis in KO versus WT hearts, as assessed by TUNEL staining. (I) Echocardiographic analysis. Data are mean ± SEM; numbers within bars denote n. *P < 0.05. Scale bars: 100 μm.

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