Abstract Body: Background
TEA domain transcriptional factor-1 (TEAD1) is a nuclear binding partner of YAP, the nuclear effector of the Hippo pathway. The role of TEAD1 during pathological hypertrophy remains unclear.
Aim
We will investigate the role of TEAD1 in heart failure during pressure overload (PO).
Results
Mice were subjected to PO via transverse aortic constriction (TAC). In wild type (WT) mice, TEAD1 was increased after 1 week and peaked after 4 weeks (1.7-fold, p<0.05 vs baseline). YAP was increased after 1 day, peaked at 1 week, and returned to baseline at 4 weeks. TEAD1 bound to YAP after 1 week but not 4 weeks of PO. Ser127 phosphorylation of YAP was not increased at 1 week but was increased after 4 weeks of PO, suggesting that YAP is activated during the acute phase but inactivated during the chronic phase. Heterozygous cardiac-specific TEAD1 knockout (TEAD1chKO) mice have normal cardiac function at baseline, but developed cardiac dysfunction compared to WT mice after 1 week of PO (left ventricular (LV) ejection fraction (LVEF): 39 ± 2.6 vs 52 ± 2.0 %, p<0.05). Cardiac fibrosis and apoptosis were increased in TEAD1chKO mice compared to in WT mice at 1 week (Fibrosis: 3.3 ± 0.13 vs 2.2 ± 0.18, TUNEL: 0.13 ± 0.01 %, p<0.05 vs 0.08 ± 0.01, p<0.05). However, after 4 weeks of PO, although cardiac function was still worse in TEAD1chKO mice, cardiac fibrosis and the number of apoptotic cardiomyocytes were lower in TEAD1chKO than in WT mice. To investigate the specific role of TEAD1 during the chronic phase of PO, we generated tamoxifen-inducible TEAD1chKO mice. TEAD1 downregulation after 1 week of TAC improved cardiac function and decreased LV dilation compared to in WT mice after 4 weeks of PO (LVEF: 56 ± 1.2 vs 36 ± 1.4 %, p<0.05). Cardiac fibrosis and the number of apoptotic cardiomyocytes were decreased in tamoxifen-induced TEAD1chKO mice (Fibrosis: 4.4 ± 0.46 vs 2.8 ± 0.39 %, TUNEL: 0.06 ± 0.01 vs 0.09 ± 0.01 %, p<0.05), and cardiac inflammation, evaluated with RNA-sequencing analyses, was reduced compared to in WT mice after PO. Our data shows that TEAD1 binds to YAP and mediates adaptive cardiac hypertrophy in the acute phase of PO but promotes cardiac inflammation, thereby promoting heart failure, in the chronic phase of PO.
Conclusion
TEAD1 plays multiple roles in a time-dependent manner during the development of heart failure. TEAD1 inhibition may represent a novel therapeutic strategy for heart failure during the chronic phase.