MiR-30 promotes fatty acid beta-oxidation and endothelial cell dysfunction and is a circulating biomarker of coronary microvascular dysfunction in pre-clinical models of diabetes.
MiR-30 promotes fatty acid beta-oxidation and endothelial cell dysfunction and is a circulating biomarker of coronary microvascular dysfunction in pre-clinical models of diabetes.pdf
Biomarker; Diabetes; Diastolic dysfunction; Endothelial cell; Extracellular vesicle; Heart failure with preserved ejection fraction; Microvasculature; microRNA; Biomarkers; Fatty Acids; MIRN30 microRNA, rat; MicroRNAs; Mirn30d microRNA, mouse; Animals; Endothelial Cells/metabolism; Endothelial Cells/pathology; Fatty Acids/metabolism; Mice; Rats; Stroke Volume; Diabetes Mellitus, Type 2/diagnosis; Diabetes Mellitus, Type 2/genetics; Heart Failure; MicroRNAs/genetics; MicroRNAs/metabolism; Diabetes Mellitus, Type 2; Endothelial Cells; Internal Medicine; Endocrinology, Diabetes and Metabolism; Cardiology and Cardiovascular Medicine
Abstract :
[en] BACKGROUND: Type 2 diabetes (T2D) is associated with coronary microvascular dysfunction, which is thought to contribute to compromised diastolic function, ultimately culminating in heart failure with preserved ejection fraction (HFpEF). The molecular mechanisms remain incompletely understood, and no early diagnostics are available. We sought to gain insight into biomarkers and potential mechanisms of microvascular dysfunction in obese mouse (db/db) and lean rat (Goto-Kakizaki) pre-clinical models of T2D-associated diastolic dysfunction.
METHODS: The microRNA (miRNA) content of circulating extracellular vesicles (EVs) was assessed in T2D models to identify biomarkers of coronary microvascular dysfunction/rarefaction. The potential source of circulating EV-encapsulated miRNAs was determined, and the mechanisms of induction and the function of candidate miRNAs were assessed in endothelial cells (ECs).
RESULTS: We found an increase in miR-30d-5p and miR-30e-5p in circulating EVs that coincided with indices of coronary microvascular EC dysfunction (i.e., markers of oxidative stress, DNA damage/senescence) and rarefaction, and preceded echocardiographic evidence of diastolic dysfunction. These miRNAs may serve as biomarkers of coronary microvascular dysfunction as they are upregulated in ECs of the left ventricle of the heart, but not other organs, in db/db mice. Furthermore, the miR-30 family is secreted in EVs from senescent ECs in culture, and ECs with senescent-like characteristics are present in the db/db heart. Assessment of miR-30 target pathways revealed a network of genes involved in fatty acid biosynthesis and metabolism. Over-expression of miR-30e in cultured ECs increased fatty acid β-oxidation and the production of reactive oxygen species and lipid peroxidation, while inhibiting the miR-30 family decreased fatty acid β-oxidation. Additionally, miR-30e over-expression synergized with fatty acid exposure to down-regulate the expression of eNOS, a key regulator of microvascular and cardiomyocyte function. Finally, knock-down of the miR-30 family in db/db mice decreased markers of oxidative stress and DNA damage/senescence in the microvascular endothelium.
CONCLUSIONS: MiR-30d/e represent early biomarkers and potential therapeutic targets that are indicative of the development of diastolic dysfunction and may reflect altered EC fatty acid metabolism and microvascular dysfunction in the diabetic heart.
Disciplines :
Cardiovascular & respiratory systems
Author, co-author :
Veitch, Shawn ✱; Department of Laboratory Medicine & Pathobiology, University of Toronto, Toronto, ON, Canada ; Toronto General Hospital Research Institute, University Health Network, Toronto, ON, Canada
Njock, Makon-Sébastien ✱; Université de Liège - ULiège > GIGA > GIGA I3 - Pneumology ; Toronto General Hospital Research Institute, University Health Network, Toronto, ON, Canada
Chandy, Mark ✱; Toronto General Hospital Research Institute, University Health Network, Toronto, ON, Canada ; Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA, USA
Siraj, M Ahsan; Toronto General Hospital Research Institute, University Health Network, Toronto, ON, Canada
Chi, Lijun; Translational Medicine, The Hospital for Sick Children, Toronto, ON, Canada
Mak, HaoQi; Department of Laboratory Medicine & Pathobiology, University of Toronto, Toronto, ON, Canada ; Toronto General Hospital Research Institute, University Health Network, Toronto, ON, Canada
Yu, Kai; Toronto General Hospital Research Institute, University Health Network, Toronto, ON, Canada
Rathnakumar, Kumaragurubaran; Toronto General Hospital Research Institute, University Health Network, Toronto, ON, Canada
Perez-Romero, Carmina Anjelica; Translational Medicine, The Hospital for Sick Children, Toronto, ON, Canada
Chen, Zhiqi; Toronto General Hospital Research Institute, University Health Network, Toronto, ON, Canada
Alibhai, Faisal J; Toronto General Hospital Research Institute, University Health Network, Toronto, ON, Canada
Gustafson, Dakota; Department of Laboratory Medicine & Pathobiology, University of Toronto, Toronto, ON, Canada ; Toronto General Hospital Research Institute, University Health Network, Toronto, ON, Canada
Raju, Sneha; Toronto General Hospital Research Institute, University Health Network, Toronto, ON, Canada
Wu, Ruilin; Department of Laboratory Medicine & Pathobiology, University of Toronto, Toronto, ON, Canada ; Toronto General Hospital Research Institute, University Health Network, Toronto, ON, Canada
Zarrin Khat, Dorrin; Department of Laboratory Medicine & Pathobiology, University of Toronto, Toronto, ON, Canada ; Toronto General Hospital Research Institute, University Health Network, Toronto, ON, Canada
Wang, Yaxu; Translational Medicine, The Hospital for Sick Children, Toronto, ON, Canada
Caballero, Amalia; Translational Medicine, The Hospital for Sick Children, Toronto, ON, Canada
Meagher, Patrick; Keenan Biomedical Research Centre, Li Ka Shing Knowledge Institute, St. Michael's Hospital, University of Toronto, Toronto, ON, Canada
Lau, Edward; Department of Medicine, Division of Cardiology, University of Colorado School of Medicine, Aurora, CO, USA
Pepic, Lejla; Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA, USA
Cheng, Henry S; Department of Laboratory Medicine & Pathobiology, University of Toronto, Toronto, ON, Canada ; Toronto General Hospital Research Institute, University Health Network, Toronto, ON, Canada
Galant, Natalie J; Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada
Howe, Kathryn L; Toronto General Hospital Research Institute, University Health Network, Toronto, ON, Canada ; Peter Munk Cardiac Centre, University Health Network, Toronto, ON, Canada
Li, Ren-Ke; Toronto General Hospital Research Institute, University Health Network, Toronto, ON, Canada
Connelly, Kim A; Translational Medicine, The Hospital for Sick Children, Toronto, ON, Canada
Husain, Mansoor; Toronto General Hospital Research Institute, University Health Network, Toronto, ON, Canada
Delgado-Olguin, Paul; Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA, USA ; Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada
Fish, Jason E ; Department of Laboratory Medicine & Pathobiology, University of Toronto, Toronto, ON, Canada. jason.fish@utoronto.ca ; Toronto General Hospital Research Institute, University Health Network, Toronto, ON, Canada. jason.fish@utoronto.ca ; Peter Munk Cardiac Centre, University Health Network, Toronto, ON, Canada. jason.fish@utoronto.ca
✱ These authors have contributed equally to this work.
Language :
English
Title :
MiR-30 promotes fatty acid beta-oxidation and endothelial cell dysfunction and is a circulating biomarker of coronary microvascular dysfunction in pre-clinical models of diabetes.
This work was supported by seed and team grant funding from the Canadian Vascular Network (to MH and JEF), a seed grant from the Ted Rogers Centre for Heart Research (TRCHR) (to PDO and JEF), and project grants from the Canadian Institutes of Health Research (CIHR) (to JEF; PJT148487 and PJT173489). JEF received infrastructure funding from the John R. Evans Leaders Fund and the Ontario Research Fund (Canada Foundation for Innovation) and is the recipient of a Tier II Canada Research Chair from CIHR. SV received funding from the Ontario Graduate Scholarship program and the TRCHR. M-SN received post-doctoral funding from the TRCHR and the Toronto General Hospital Research Institute. MC was supported by the Clinician Scientist Training Program and the Detweiler Traveling Fellowship from the Royal College of Physicians and Surgeons. DG received a Canada Graduate Scholarship from CIHR, an Ontario Graduate Scholarship and a studentship from TRCHR. FJA is supported by a CIHR post-doctoral fellowship. KR received post-doctoral fellowships from the Canadian Vascular Network and the TRCHR. PDO is supported by the Canadian Institutes of Health Research (CIHR) (PJT162208 and PJT149046), the Heart and Stroke Foundation of Canada (G-17-0018613), and the Natural Sciences and Engineering Research Council of Canada (NSERC) (500865). KAC is supported by a Merit Award from the Department of Medicine, the University of Toronto. The funding bodies did not play a role in the design of the study, analysis or interpretation of the data, nor did they play a role in the writing of the manuscript.
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