<i>Yap1</i> modulates cardiomyocyte hypertrophy via impaired mitochondrial biogenesis in response to chronic mechanical stress overload

Abstract

<b>Rationale:</b> 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. <b>Methods:</b> 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 <i>Yap1^F/F</i> mice to induce mosaic depletion of YAP1. <i>Myh6^CreERT2; H11^CAG-LSL-YAP1</i> 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. <i>Dnm1l</i> and <i>Mfn1</i> 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. <b>Results:</b> We found that pathological hypertrophy was accompanied with the activation of YAP1. Cardiomyocyte-specific deletion of <i>Yap1</i> 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 <i>Dnm1l</i> and <i>Mfn1</i>. Mitochondrial-related genes <i>Dnm1l</i> and <i>Mfn1</i>, are significantly targeted by TEAD1/YAP complex. Overexpression of <i>Dnm1l</i> and <i>Mfn1</i> 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. <b>Conclusion:</b> 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.