Yap1 modulates cardiomyocyte hypertrophy via impaired mitochondrial biogenesis in response to chronic mechanical stress overload.

Chronic pressure overload is a major trigger of cardiac pathological hypertrophy that eventually leads to heart disease and heart failure. Understanding the mechanisms governing hypertrophy is the key to develop therapeutic strategies for heart diseases. We built chronic pressure overload mice model by abdominal aortic constriction (AAC) to explore the features of Yes-associated protein 1 (YAP1). Then AAV-cTNT-Cre was applied to mice to induce mosaic depletion of YAP1. mice were involved to establish YAP1 overexpression model by Tomaxifen injection. ATAC-seq and bioChIP-seq were used to explore the potential targets of YAP1, which were verified by a series of luciferase reporter assays. and were re-expressed in AAC mice by AAV-cTNT-Dnm1l and AAV-cTNT-Mfn1. Finally, Verteprofin was used to inhibit YAP1 to rescue cardiac hypertrophy. We found that pathological hypertrophy was accompanied with the activation of YAP1. Cardiomyocyte-specific deletion of attenuated AAC-induced hypertrophy. Overexpression of YAP1 was sufficient to phenocopy AAC-induced hypertrophy. YAP1 activation resulted in the perturbation of mitochondria ultrastructure and function, which was associated with the repression of mitochondria dynamics regulators and . Mitochondrial-related genes and , are significantly targeted by TEAD1/YAP complex. Overexpression of and synergistically rescued YAP1-induced mitochondrial damages and cardiac hypertrophy. Pharmacological repression of YAP1 by verteporfin attenuated mitochondrial damages and pathological hypertrophy in AAC-treated mice. Interestingly, YAP1-induced mitochondria damages also led to increased reactive oxidative species, DNA damages, and the suppression of cardiomyocyte proliferation. Together, these data uncovered YAP signaling as a therapeutic target for pressure overload-induced heart diseases and cautioned the efforts to induce cardiomyocyte regeneration by activating YAP.