Abstract 20449: Proapoptotic Rassf1A/Mst1 Signaling in Cardiac Fibroblasts is Protective Against Pressure Overload in Mice
Mammalian sterile 20 like kinase 1 (Mst1) promotes apoptosis and inhibits compensatory cardiac hypertrophy, thereby playing a critical role in mediating heart failure. However, the regulation of Mst1 in the heart is poorly understood. The goal of this study was to elucidate the role of the tumor suppressor Rassf1A in activating Mst1 in the heart and modulating cardiac growth and death in response to pressure overload (PO). PO elicited Mst1 activation (3.4 ± 0.9 fold vs. Sham, p<0.05, n=5), a response that was abolished in mice lacking Rassf1A (decreased 92 ± 12% in KO vs WT, p<0.05, n=5). Cardiac expression of Rassf1A activated Mst1 (4.6 ± 1.4 fold vs NTG, p<0.05, n=4) and exaggerated dysfunction following PO (LVEF%, 72 ± 3% NTG vs 60 ± 5% SF1A TG, p<0.05, n=8) , while expression of L308P Rassf1A, which cannot associate with Mst1, prevented Mst1 activation (inhibited 85 ± 14% vs NTG, p<0.05, n=3) and maintained function after PO (LVEF%, 71 ± 3% NTG vs 78 ± 1% L308P, p<0.05, n=5). Surprisingly, we observed increased PO-induced fibrosis (7.1 ± 2.5% in WT vs 19.1 ± 2.8% in KO, p<0.05, n=4) and cardiac hypertrophy (LVW/TL, 7.6 ± 0.4 in WT vs 9.2 ± 0.4 in KO, p<0.05, n=6) in systemically deleted rassf1A mice; however, fibrosis (7.5 ± 2.4% in WT vs 1.6 ± 0.7% in CKO, p<0.05, n=3) and cardiac hypertrophy were inhibited (LVW/TL, 6.3 ± 0.2 in WT vs 5.1 ± 0.2 in CKO, p<0.05, n=6) in mice lacking rassf1A specifically in cardiomyocytes. Examination of Rassf1A/Mst1 signaling in cardiac fibroblasts revealed that Rassf1/Mst1 negatively regulates NF-κB signaling and secretion of TNF-α in cardiac fibroblasts. Neutralization of TNF-α by injection of TNF-α blocking antibody was sufficient to rescue the exaggerated hypertrophy (LVW/TL, 9.8 ± 0.3 in IgG vs 8.1 ± 0.4 in anti-TNF-α, p<0.05, n=5) and fibrotic phenotype (22 ± 4.7% in IgG vs 8.1 ± 1.9% in anti-TNF-α, p<0.05, n=5) of systemic rassf1A KO mice caused by PO, implicating TNF-α as a key mediator of Rassf1A/Mst1 signaling. In summary, the functional consequences of activating Rassf1A/Mst1 during PO are cell type-dependent. Although activation of Rassf1A/Mst1 in cardiomyocytes is detrimental through induction of apoptosis, in fibroblasts it is salutary through downregulation of TNF-α and consequent suppression of cardiac hypertrophy and fibrosis.
- © 2010 by American Heart Association, Inc.