Abstract 1785: NF2 Plays Detrimental Roles through Mst1 against Pressure Overload (PO) in the Heart
Neurofibromatosis type 2 (NF2) is a tumor suppressor gene involved in organization of the membrane and cytoskeleton. The cellular function of NF2 in the heart is not well understood. In Drosophila, NF2 acts as an upstream regulator of Hpo, a homolog of mammalian sterile 20-like kinase 1 (Mst1). Since Mst1 plays an essential role in mediating apoptosis and left ventricular (LV) dysfunction in the heart, we examined whether NF2 regulates cardiac myocyte apoptosis and heart failure. In order to investigate the function of endogenous NF2, we used NF2 ± mice. NF2 ± mice did not exhibit obvious cardiac phenotype at baseline. Protein expression of NF2 in the heart was upregulated 1.3 fold (p<0.05) in response to transverse aortic constriction (TAC) for 4 weeks in wild type (WT) mice, whereas the upregulation of NF2 was abolished in NF2 ± mice. Pressure gradients were comparable between NF2 ± and WT mice (89±9 vs 79±8 mmHg, n=8, 7). Neither LV weight (LVW) /tibial length (TL) (7.9±0.3 vs 8.5±0.4, n=8, 7) nor myocyte cross sectional area were significantly different between NF2 ± and WT mice after TAC for 4 weeks. Interestingly, LV ejection fraction (LVEF) was significantly greater (63±2% vs 55±2%, p<0.05, n=8, 7) and lung weight /TL (9.9±0.2 vs11.5±0.4, p<0.05, n=8, 7) was significantly smaller in NF2 ± than in WT mice. LV interstitial fibrosis (3% vs 10%, p<0.05, n=4) was significantly less in NF2± than in WT mice. mRNA expression of atrial natriuretic factor was significantly lower in NF2± than in WT mice (p<0.05, n=3). The number of TUNEL positive cells (0.01% vs 0.09%, p<0.05, n=4) was significantly smaller in NF2± than in WT mice. Thus, downregulation of NF2 is protective for the heart against PO. Interestingly, the activity of Mst1 after TAC, as determined by Thr 183 phosphorylation, was significantly decreased in NF2 ± compared to WT mice (0.7 fold, p<0.05), suggesting that the activity of Mst1 is critically regulated by NF2. These results suggest that NF2 promotes cardiac dysfunction under PO by promoting apoptosis and fibrosis without affecting hypertrophy in the mouse heart. Furthermore, NF2 positively regulates the activity of Mst1, a major pro-apoptotic kinase, in cardiac myocytes. Thus, NF2 may be an important target for treatment of heart failure.
This research has received full or partial funding support from the American Heart Association, AHA National Center.