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

Peng Yue; Yue Zhang; Lei Liu; Kaiyu Zhou; Shutao Xia; Mou Peng; Hualin Yan; Xiaoqiang Tang; Zhan Chen; Donghui Zhang; Junling Guo; William T Pu; Yuxuan Guo; Yimin Hua; Yifei Li

doi:10.7150/thno.74563

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

Theranostics. 2022 Oct 3;12(16):7009-7031. doi: 10.7150/thno.74563. eCollection 2022.

Authors

Peng Yue¹, Yue Zhang¹, Lei Liu¹, Kaiyu Zhou¹, Shutao Xia², Mou Peng¹, Hualin Yan³, Xiaoqiang Tang¹, Zhan Chen⁴, Donghui Zhang², Junling Guo⁵, William T Pu^{6

7}, Yuxuan Guo⁴, Yimin Hua¹, Yifei Li¹

Affiliations

¹ Key Laboratory of Birth Defects and Related Diseases of Women and Children of MOE, Department of Pediatrics, West China Second University Hospital, Sichuan University, Chengdu, Sichuan 610041, China.
² State Key Laboratory of Biocatalysis and Enzyme Engineering, School of Life Science, Hubei University, Wuhan, Hubei 430062, China.
³ Department of Medical Ultrasound, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China.
⁴ Peking University Health Science Center, School of Basic Medical Sciences, The Institute of Cardiovascular Sciences, Key Laboratory of Molecular Cardiovascular Science of Ministry of Education, Beijing Key Laboratory of Cardiovascular Receptors Research, Beijing, 100191, China.
⁵ BMI Center for Biomass Materials and Nanointerfaces, College of Biomass Science and Engineering, Sichuan University, Chengdu, Sichuan 610065, China.
⁶ Department of Cardiology, Boston Children's Hospital, Boston, MA 02115 USA.
⁷ Harvard Stem Cell Institute, Harvard University, Cambridge, MA 02138 USA.

Abstract

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.

Keywords: Verteporfin; YAP signaling; mitochondria; pathological hypertrophy.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Cardiomegaly / metabolism
Mice
Myocytes, Cardiac* / metabolism
Organelle Biogenesis*
Stress, Mechanical
Verteporfin / pharmacology
YAP-Signaling Proteins* / genetics

Substances

Verteporfin
YAP-Signaling Proteins