Loss of the long non-coding RNA OIP5-AS1 exacerbates heart failure in a sex-specific manner
Aowen Zhuang,
Anna C. Calkin,
Shannen Lau,
Helen Kiriazis,
Daniel G. Donner,
Yingying Liu,
Simon T. Bond,
Sarah C. Moody,
Eleanor A.M. Gould,
Timothy D. Colgan,
Sergio Ruiz Carmona,
Michael Inouye,
Thomas Q. de Aguiar Vallim,
Elizabeth J. Tarling,
Gregory A. Quaife-Ryan,
James E. Hudson,
Enzo R. Porrello,
Paul Gregorevic,
Xiao-Ming Gao,
Xiao-Jun Du,
Julie R. McMullen,
Brian G. Drew
Affiliations
Aowen Zhuang
Baker Heart & Diabetes Institute, Melbourne, VIC 3004, Australia; Central Clinical School, Monash University, Melbourne, VIC 3004, Australia
Anna C. Calkin
Baker Heart & Diabetes Institute, Melbourne, VIC 3004, Australia; Central Clinical School, Monash University, Melbourne, VIC 3004, Australia
Shannen Lau
Baker Heart & Diabetes Institute, Melbourne, VIC 3004, Australia
Helen Kiriazis
Baker Heart & Diabetes Institute, Melbourne, VIC 3004, Australia
Daniel G. Donner
Baker Heart & Diabetes Institute, Melbourne, VIC 3004, Australia
Yingying Liu
Baker Heart & Diabetes Institute, Melbourne, VIC 3004, Australia
Simon T. Bond
Baker Heart & Diabetes Institute, Melbourne, VIC 3004, Australia
Sarah C. Moody
Baker Heart & Diabetes Institute, Melbourne, VIC 3004, Australia
Eleanor A.M. Gould
Baker Heart & Diabetes Institute, Melbourne, VIC 3004, Australia
Timothy D. Colgan
Baker Heart & Diabetes Institute, Melbourne, VIC 3004, Australia
Sergio Ruiz Carmona
Baker Heart & Diabetes Institute, Melbourne, VIC 3004, Australia
Michael Inouye
Baker Heart & Diabetes Institute, Melbourne, VIC 3004, Australia; Department of Public Health and Primary Care, University of Cambridge, Cambridge, CB1 8RN, UK
Thomas Q. de Aguiar Vallim
Department of Medicine, University of California Los Angeles, Los Angeles, CA 90095, USA
Elizabeth J. Tarling
Department of Medicine, University of California Los Angeles, Los Angeles, CA 90095, USA
Gregory A. Quaife-Ryan
QIMR Berghofer, Brisbane, QLD 4072, Australia
James E. Hudson
QIMR Berghofer, Brisbane, QLD 4072, Australia
Enzo R. Porrello
Murdoch Children's Research Institute, Parkville, VIC 3052, Australia; Centre for Muscle Research, Department of Anatomy and Physiology, School of Biomedical Sciences, University of Melbourne, Parkville, VIC 3010, Australia
Paul Gregorevic
Baker Heart & Diabetes Institute, Melbourne, VIC 3004, Australia; Centre for Muscle Research, Department of Anatomy and Physiology, School of Biomedical Sciences, University of Melbourne, Parkville, VIC 3010, Australia
Xiao-Ming Gao
Baker Heart & Diabetes Institute, Melbourne, VIC 3004, Australia
Xiao-Jun Du
Baker Heart & Diabetes Institute, Melbourne, VIC 3004, Australia
Julie R. McMullen
Baker Heart & Diabetes Institute, Melbourne, VIC 3004, Australia; Central Clinical School, Monash University, Melbourne, VIC 3004, Australia; Corresponding author
Brian G. Drew
Baker Heart & Diabetes Institute, Melbourne, VIC 3004, Australia; Central Clinical School, Monash University, Melbourne, VIC 3004, Australia; Corresponding author
Summary: Long non-coding RNAs (lncRNAs) have been demonstrated to influence numerous biological processes, being strongly implicated in the maintenance and physiological function of various tissues including the heart. The lncRNA OIP5-AS1 (1700020I14Rik/Cyrano) has been studied in several settings; however its role in cardiac pathologies remains mostly uncharacterized. Using a series of in vitro and ex vivo methods, we demonstrate that OIP5-AS1 is regulated during cardiac development in rodent and human models and in disease settings in mice. Using CRISPR, we engineered a global OIP5-AS1 knockout (KO) mouse and demonstrated that female KO mice develop exacerbated heart failure following cardiac pressure overload (transverse aortic constriction [TAC]) but male mice do not. RNA-sequencing of wild-type and KO hearts suggest that OIP5-AS1 regulates pathways that impact mitochondrial function. Thus, these findings highlight OIP5-AS1 as a gene of interest in sex-specific differences in mitochondrial function and development of heart failure.
