Key result
YAP1 deletion or verteporfin attenuates pressure overload-induced pathological cardiac hypertrophy and mitochondrial dysfunction.
Why the study?
Chronic pressure overload triggers cardiac pathological hypertrophy leading to heart disease and heart failure, but mechanisms governing hypertrophy remain to be fully understood.
Does YAP1 modulation or pharmacological repression by verteporfin prevent cardiomyocyte hypertrophy in response to chronic mechanical stress overload?
Does YAP1 modulation or pharmacological repression by verteporfin prevent cardiomyocyte hypertrophy in response to chronic mechanical stress overload?
YAP1 signaling mediates pressure overload-induced cardiac hypertrophy via impaired mitochondrial biogenesis, highlighting it as a potential therapeutic target and cautioning against its activation for cardiomyocyte regeneration.
Answers are grounded in this paper and cite their sources.
Hypothesis-generating for YAP1 inhibition in hypertrophy; leaves open translation to human pressure-overload states.
Rationale: 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.Methods: 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 Yap1 F/F mice to induce mosaic depletion of YAP1.Myh6 CreERT2 ; H11 CAG-LSL-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.Dnm1l and Mfn1 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.Results: We found that pathological hypertrophy was accompanied with the activation of YAP1.Cardiomyocyte-specific deletion of Yap1 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 Dnm1l and Mfn1.Mitochondrial-related genes Dnm1l and Mfn1, are significantly targeted by TEAD1/YAP complex.Overexpression of Dnm1l and Mfn1 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.Conclusion: 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.
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Zhang et al. (2022) studied Cardiac pathological hypertrophy. YAP1 modulation (genetic deletion, overexpression, or pharmacological inhibition with verteporfin) vs. Sham surgery, control AAV, or vehicle was evaluated on Cardiomyocyte hypertrophy and mitochondrial dysfunction. YAP1 activation drives pressure overload-induced pathological cardiac hypertrophy and mitochondrial dysfunction, which can be attenuated by YAP1 deletion or pharmacological inhibition with verteporfin.
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