Author + information
- Received November 14, 2017
- Revision received December 13, 2017
- Accepted December 21, 2017
- Published online April 30, 2018.
- Dimosthenis Giamouridis, BS, MSa,b,c,
- Mei Hua Gao, PhDa,b,
- N. Chin Lai, PhDa,b,
- Zhen Tan, PhDa,b,
- Young Chul Kim, PhDa,b,
- Tracy Guo, BSa,b,
- Atsushi Miyanohara, PhDb,
- W. Matthijs Blankesteijn, PhDc,
- Erik Biessen, PhDc and
- H. Kirk Hammond, MDa,b,∗ ()
- aDepartment of Medicine, Veterans Affairs San Diego Healthcare System, San Diego, California
- bDepartment of Medicine, University of California San Diego, San Diego, California
- cDepartment of Pharmacology and Toxicology, Cardiovascular Research Institute Maastricht University, Maastricht, the Netherlands
- ↵∗Address for correspondence:
Dr. H. Kirk Hammond, Department of Medicine (111A), University of California-San Diego, Veterans Affairs San Diego Healthcare System, 3350 La Jolla Village Drive, San Diego, California 92161.
• UCn2 and UCn3 gene transfer increased LV peak +dP/dt (systolic function) and LV peak −dP/dt (diastolic function) significantly and similarly.
• Both genes increased LV levels of SERCA2a, and isolated cardiac myocytes showed similar favorable effects on Ca2+ transients.
• UCn2, but not UCn3, gene transfer reduced fasting glucose and increased glucose disposal.
• These findings support UCn2 and UCn3 gene transfer as potential treatments for heart failure and indicate that UCn2 may be an optimal selection in patients with diabetes and heart failure.
UCn2 and UCn3 peptides have recently been infused to treat patients with heart failure (HF) but are limited by their short half-lives. A 1-time intravenous injection of virus vectors encoding UCn2 or UCn3 provided sustained increases in plasma concentrations of the peptides. This was associated with increases in both systolic and diastolic left ventricular (LV) function, mediated by increased LV SERCA2a expression and Ca2+ handling. UCn2, but not UCn3, gene transfer reduced fasting glucose and increased glucose disposal. These findings support UCn2 and UCn3 gene transfer as potential treatments for HF and indicate that UCn2 may be an optimal selection in patients with diabetes and HF.
This work was supported by National Institutes of Health grants P01 HL66941 and R42HL122038; National Heart, Lung, and Blood Institute Gene Therapy Resource Program grant HHSN268201200041C; and Department of Veteran’s Affairs Merit grants 1I01 BX001515-03 and 1I01 BX003774-01A1. Dr. Hammond is a founder and unpaid consultant of Renova Therapeutics, which played no role in the studies. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
All 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 November 14, 2017.
- Revision received December 13, 2017.
- Accepted December 21, 2017.
- 2018 The Authors