Author + information
- Received July 9, 2017
- Revision received August 29, 2017
- Accepted September 11, 2017
- Published online February 26, 2018.
- Janet R. Manning, PhDa,b,
- Lakshman Chelvarajan, PhDc,
- Bryana M. Levitan, BAa,d,
- Catherine N. Withers, PhDb,
- Prabhakara R. Nagareddy, PhDe,
- Christopher M. Haggerty, PhDc,f,
- Brandon K. Fornwalt, MD, PhDc,f,
- Erhe Gao, MD, PhDg,
- Himi Tripathi, PhDc,
- Ahmed Abdel-Latif, MD, PhDc,d,
- Douglas A. Andres, PhDb and
- Jonathan Satin, PhDa,∗ ()
- aDepartment of Physiology, University of Kentucky, Lexington, Kentucky
- bDepartment of Biochemistry, University of Kentucky, Lexington, Kentucky
- cSaha Cardiovascular Research Center, Department of Medicine, University of Kentucky, Lexington, Kentucky
- dGill Heart and Vascular Institute, University of Kentucky, Lexington, Kentucky
- eDepartment of Nutrition Sciences, University of Alabama, Birmingham, Alabama
- fDepartment of Imaging Science and Innovation, Geisinger, Danville, Pennsylvania
- gCenter for Translational Medicine, Temple University School of Medicine, Philadelphia, Pennsylvania
- ↵∗Address for correspondence:
Dr. Jonathan Satin, Department of Physiology, MS-508, University of Kentucky College of Medicine, 800 Rose Street, Lexington, Kentucky 40536-0298.
• Rad-GTPase is an LTCC component that functions to govern calcium current in the myocardium.
• Deletion of Rad increases myocardial contractility secondary to increased trigger calcium entry.
• AMI induces heart failure, including reduced calcium homeostasis, but deletion of Rad prevents AMI myocardial calcium alterations.
• Rad deletion prevents post-MI scar spread by attenuating the inflammatory response.
• Future studies will explore whether Rad deletion is an effective therapeutic direction for providing combined safe, stable inotropic support to the failing heart in concert with protection against inflammatory signaling.
The protein Rad interacts with the L-type calcium channel complex to modulate trigger Ca2+ and hence to govern contractility. Reducing Rad levels increases cardiac output. Ablation of Rad also attenuated the inflammatory response following acute myocardial infarction. Future studies to target deletion of Rad in the heart could be conducted to establish a novel treatment paradigm whereby pathologically stressed hearts would be given safe, stable positive inotropic support without arrhythmias and without pathological structural remodeling. Future investigations will also focus on establishing inhibitors of Rad and testing the efficacy of Rad deletion in cardioprotection relative to the time of onset of acute myocardial infarction.
Dr. Manning has received grants from the American Heart Association (14POST20460224) and the NIH (F32HL126300). Dr. Withers has received an NIH grant (T32-HL0727423) and an NSF grant (DGE-1247392). Dr. Nagareddy has received an NIH grant (R00 HL22505). Dr. Abdel-Latif has received NIH grants (UK Cobre NIH P20 GM 103527 and NIH R56 HL124266). Drs. Withers and Andres has received the IDeA award 8 P20 GM103527. Drs. Andres and Satin have received grants from the NIH (R56HL131782) and the American Heart Association (GRNT27790094). Dr. Andres has received a UK Research Professorship. Dr. Satin has received an NIH grant (R01 HL074091). 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 July 9, 2017.
- Revision received August 29, 2017.
- Accepted September 11, 2017.
- 2018 The Authors