©The Author(s) 2017. Published by Baishideng Publishing Group Inc. All rights reserved.
Interleukin-19 is cardioprotective in dominant negative cyclic adenosine monophosphate response-element binding protein-mediated heart failure in a sex-specific manner
Danielle R Bruns, Alexander R Ghincea, Christian V Ghincea, Yasu-Taka Azuma, Peter A Watson, Michael V Autieri, Lori A Walker
Danielle R Bruns, Alexander R Ghincea, Christian V Ghincea, Lori A Walker, Division of Cardiology, Department of Medicine, University of Colorado-Denver, Aurora, CO 80045, United States
Yasu-Taka Azuma, Laboratory of Veterinary Pharmacology, Division of Veterinary Science, Osaka Prefecture University Graduate School of Life and Environmental Science, Osaka 599-8351, Japan
Peter A Watson, Department of Medicine and Endocrinology, University of Colorado-Denver, Aurora, CO 80045, United States
Peter A Watson, Denver Veterans Affairs Medical Center, Denver, CO 80220, United States
Michael V Autieri, Independence Blue Cross Cardiovascular Research Center, Department of Physiology, Temple University School of Medicine, Philadelphia, PA 19122, United States
Author contributions: Bruns DR was involved in conception and design of research, collected, analyzed, and interpreted data, and drafted the manuscript; Ghincea AR and Ghincea CV collected data; Azuma YT approved the final manuscript; Watson PA was involved in conception and design of research; Autieri MV contributed to intellectual design of research, edited and revised final manuscript; Walker LA was involved in conception and design of research, interpretation of data, editing, revising, and approval of final manuscript.
Supported by The University of Colorado-Denver Center for Women’s Health Research (to Walker LA); NIH NHLBI HL007822-19 (to Bruns DR); NIH NHLBI HL117724 (to Autieri MV); NIH NHLBI HL115575 (to Autieri MV).
Institutional review board statement: Human subjects research is governed by the Colorado Multiple Institutional Review Board (COMIRB # IORG0000433). However, no human subjects were included in this research.
Institutional animal care and use committee statement: All procedures involving animals were reviewed and approved by the Institutional Animal Care and Use Committee at the University of Colorado-Denver [Protocol # B-78616(05)1D].
Conflict-of-interest statement: The authors declare that they have no competing interests.
Data sharing statement: Complete dataset and statistical analyses available from the corresponding author at lori.walker@ucdenver.edu.
Correspondence to: Lori A Walker, PhD, Division of Cardiology, Department of Medicine, University of Colorado-Denver, 12700 E. 19
th Ave, Aurora, CO 80045, United States.
lori.walker@ucdenver.edu
Telephone: +1-303-7245420
Received: January 11, 2017
Peer-review started: January 16, 2017
First decision: April 17, 2017
Revised: July 19, 2017
Accepted: July 21, 2017
Article in press: July 24, 2017
Published online: August 26, 2017
Processing time: 224 Days and 5.3 Hours
AIM
To investigate the role of interleukin-19 (IL-19) in a murine model of female-dominant heart failure (HF).
METHODS
Expression of one copy of a phosphorylation-deficient cyclic adenosine monophosphate response-element binding protein (dnCREB) causes HF, with accelerated morbidity and mortality in female mice compared to males. We assessed expression of IL-19, its receptor isoforms IL-20R α/β, and downstream IL-19 signaling in this model of female-dominant HF. To test the hypothesis that IL-19 is cardioprotective in dnCREB-mediated HF, we generated a novel double transgenic (DTG) mouse of dnCREB and IL-19 knockout and assessed cardiac morbidity by echocardiography and survival of male and female mice.
RESULTS
IL-19 is expressed in the murine heart with decreased expression in dnCREB female compared to male mice. Further, the relative expression of the two IL-19 receptor isoforms manifests differently in the heart by sex and by disease. Male DTG mice had accelerated mortality and cardiac morbidity compared to dnCREB males, while female DTG mice showed no additional detriment, supporting the hypothesis that IL-19 is cardioprotective in this model.
CONCLUSION
Together, these data suggest IL-19 is an important cytokine mediating sex-specific cardiac (dys) function. Ongoing investigations will elucidate the mechanism(s) of sex-specific IL-19 mediated cardiac remodeling.
Core tip: Heart failure (HF) is a sexually dimorphic disease. In a female-dominant model of HF, the do-minant negative cyclic AMP response-element binding protein (dnCREB) mouse, female mice show accelerated cardiac morbidity and mortality alongside downregulated interleukin-19 (IL-19) expression, while male mice maintain IL-19 expression and are protected against cardiac dysfunction. We generated a novel double transgenic mouse with dnCREB and IL-19 knockout to test the hypothesis that IL-19 is cardioprotective. We show accelerated cardiac morbidity only in male mice, supporting the hypothesis that IL-19 is a sex-specific cardioprotective cytokine.
