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

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

Research output: Contribution to journalArticle

72 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)3555-3567
Number of pages13
JournalJournal of Clinical Investigation
Volume120
Issue number10
DOIs
StatePublished - Oct 1 2010

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Protein Isoforms
Fibroblasts
Pressure
Cardiomegaly
Apoptosis
Organ Size
Cardiac Myocytes
Diptera
Hypertrophy
Drosophila
Fibrosis
Cell Death
Phosphotransferases
Heart Failure
Cell Proliferation
Neoplasms

All Science Journal Classification (ASJC) codes

  • Medicine(all)

Cite this

Del Re, Dominic ; Matsuda, Takahisa ; Zhai, Peiyong ; Gao, Shumin ; Clark, Geoffrey J. ; Van Der Weyden, Louise ; Sadoshima, Junichi. / Proapoptotic Rassf1A/Mst1 signaling in cardiac fibroblasts is protective against pressure overload in mice. In: Journal of Clinical Investigation. 2010 ; Vol. 120, No. 10. pp. 3555-3567.
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Proapoptotic Rassf1A/Mst1 signaling in cardiac fibroblasts is protective against pressure overload in mice. / Del Re, Dominic; Matsuda, Takahisa; Zhai, Peiyong; Gao, Shumin; Clark, Geoffrey J.; Van Der Weyden, Louise; Sadoshima, Junichi.

In: Journal of Clinical Investigation, Vol. 120, No. 10, 01.10.2010, p. 3555-3567.

Research output: Contribution to journalArticle

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