Proapoptotic Rassf1A/Mst1 signaling in cardiac fibroblasts is protective against pressure overload in mice.
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.
Del Re
Dominic P
DP
Department of Cell Biology and Molecular Medicine, Cardiovascular Research Institute, New Jersey Medical School, University of Medicine and Dentistry of New Jersey, Newark, New Jersey 07103-2714, USA.
Matsuda
Takahisa
T
Zhai
Peiyong
P
Gao
Shumin
S
Clark
Geoffrey J
GJ
Van Der Weyden
Louise
L
Sadoshima
Junichi
J
D000818:Animals; D001794:Blood Pressure; D002478:Cells, Cultured; D005347:Fibroblasts / Q000378:metabolism / Q000473:pathology; D017228:Hepatocyte Growth Factor / Q000502:physiology*; D051379:Mice; D032383:Myocytes, Cardiac / Q000378:metabolism* / Q000473:pathology; D016328:NF-kappa B / Q000037:antagonists & inhibitors; D011518:Proto-Oncogene Proteins / Q000502:physiology*; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000502:physiology*; D013312:Stress, Physiological; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics; D025521:Tumor Suppressor Proteins / Q000502:physiology*
D016328:NF-kappa B; D011518:Proto-Oncogene Proteins; C496882:RASSF1 protein, mouse; D014409:Tumor Necrosis Factor-alpha; D025521:Tumor Suppressor Proteins; C082332:macrophage stimulating protein; D017228:Hepatocyte Growth Factor