Abstract 19478: Deficiency of Yes-Associated Protein Promotes Cardiac Dysfunction in Response to Acute Pressure Overload in the Mouse Heart
Yes-Associated Protein (YAP), a downstream effector of the Hippo pathway, regulates cell proliferation and survival in mammalian cells. We have shown that cardiac-specific loss of YAP leads to increased cardiacmyocyte (CM) apoptosis and impaired hypertrophy during chronic myocardial infarction in the mouse heart. However, the role of YAP in response to acute pressure-overload (PO) has yet to be examined. Nine-week-old YAP+/fl;a-MHC-Cre (YAP-cHKO) and YAP+/fl (control) mice were subjected to transverse aortic constriction (TAC). One week later, YAP-cHKO and control mice developed similar levels of cardiac hypertrophy (left ventricular (LV) weight/tibia length: 7.1, 7.86) compared to sham (4.65, 4.73) and cross sectional area (CSA) was similarly increased by TAC in YAP-cHKO and control mice (relatively: 3.37, 3.03) compared to shams (1.03, 1.0). YAP-cHKO and control mice exhibited similar baseline LV systolic function (ejection fraction (EF): 60.2, 67%). However, YAP-cHKO mice had significantly decreased LV function after TAC compared to sham-control mice (EF: 38.7%, p<0.01) and TAC-control mice (65.5%, p<0.05). LV end diastolic pressure (mmHg) was significantly increased in YAP-cHKO mice after TAC (12±1.7, 5.3±0.7, p<0.05). Control mice had significantly increased expression of Ctgf and Ankrd1, YAP target genes, after TAC, but there was no change in Ctgf and Ankrd1 expression in YAP-cHKO mice compared to control mice after TAC. TUNEL assays showed that YAP-cHKO mice developed more apoptosis than control mice after TAC (1.2%, 0.8%, p<0.05). Masson’s Trichrome staining revealed a significant increase in interstitial fibrosis in YAP-cHKO mice heart after TAC (13.2%, 0.61%, p<0.05). LV end diastolic diameter (mm) was greater in YAP-cHKO than in control mice after TAC (3.9±0.1, 3.3±0.04), whereas LV pressure was similar, suggesting that LV wall stress was elevated in YAP-cHKO compared to in control mice. Since cardiac hypertrophy in YAP-cHKO mice is similar to that in control mice despite elevated wall stress, the lack of YAP appears to limit the extent of cardiac hypertrophy in response to increased wall stress. These data suggest that endogenous YAP plays an important role in mediating adaptive hypertrophy and protecting the heart against PO.
Author Disclosures: J. Byun: None. D.P. Del Re: None. P. Zhai: None. A. Shirakabe: None. J. Sadoshima: None.
- © 2016 by American Heart Association, Inc.