Author + information
- Shohei Ikeda, MD, PhDa,b,
- Risa Mukai, MD, PhDa,
- Wataru Mizushima, MD, PhDa,
- Peiyong Zhai, MD, PhDa,
- Shin-ichi Oka, PhDa,
- Michinari Nakamura, MD, PhDa,
- Dominic P. Del Re, PhDa,
- Sebastiano Sciarretta, MD, PhDc,d,
- Chiao-Po Hsu, MD, PhDe,
- Hiroaki Shimokawa, MD, PhDb and
- Junichi Sadoshima, MD, PhDa,∗ ()
- aDepartment of Cell Biology and Molecular Medicine, Cardiovascular Research Institute, Rutgers New Jersey Medical School, Newark, New Jersey
- bDepartment of Cardiovascular Medicine, Tohoku University Graduate School of Medicine, Sendai, Japan
- cDepartment of Medico-Surgical Sciences and Biotechnologies, Sapienza University of Rome, Latina, Italy
- dIstituto Di Ricovero e Cura a Carattere Scientifico Neuromed, Pozzilli, Italy
- eDivision of Cardiovascular Surgery, Department of Surgery, Taipei Veterans General Hospital, National Yang-Ming University School of Medicine, Taiwan
- ↵∗Address for correspondence:
Dr. Junichi Sadoshima, Department of Cell Biology and Molecular Medicine, Cardiovascular Research Institute, Rutgers New Jersey Medical School, 185 South Orange Avenue, MSB G609, Newark, New Jersey 07103.
• YAP, a terminal effector of the Hippo signaling pathway, is activated in cardiomyocytes in response to high-fat diet consumption in mice and diabetes in patients.
• Long-term activation of YAP in response to high-fat diet consumption is detrimental for the heart in the presence of pressure overload.
• Detrimental effects of YAP during pressure overload are mediated through activation of a positive feedback loop, consisting of YAP, TEAD1, and OSM, and consequent dedifferentiation of cardiomyocytes.
• Chemical inhibitors of YAP, TEAD1, or OSM may be effective in treating patients who have diabetes, high blood pressure, and metabolic syndrome to prevent heart failure syndromes.
Patients with diabetes are more prone to developing heart failure in the presence of high blood pressure than those without diabetes. Yes-associated protein (YAP), a key effector of the Hippo signaling pathway, is persistently activated in diabetic hearts, and YAP plays an essential role in mediating the exacerbation of heart failure in response to pressure overload in the hearts of mice fed a high-fat diet. YAP induced dedifferentiation of cardiomyocytes through activation of transcriptional enhancer factor 1 (TEAD1), a transcription factor. Thus, YAP and TEAD1 are promising therapeutic targets for diabetic patients with high blood pressure to prevent the development of heart failure.
Dr. Sadoshima was supported in part by U.S. Public Health Service grants HL67724, HL91469, HL11233, HL132824, and AG23039, and by the Leducq Foundation Transatlantic Network of Excellence (15CBD04). Dr. Ikeda has been supported by a postdoctoral fellowship from the Japan Heart Foundation/Bayer Yakuhin Research Grant Abroad and grants-in-aid for scientific research (18K15876). All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
The authors attest they are in compliance with human studies committees and animal welfare regulations of the authors’ institutions and Food and Drug Administration guidelines, including patient consent where appropriate. For more information, visit the JACC: Basic to Translational Science author instructions page.
- Received March 14, 2019.
- Revision received April 19, 2019.
- Accepted May 9, 2019.