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

Cardiovascular Diabetology

Shawn Veitch¹  Ruilin Wu¹  Dorrin Zarrin Khat¹  Dakota Gustafson¹  Henry S. Cheng¹  HaoQi Mak¹  Jason E. Fish²  Edward Lau³  Patrick Meagher⁴  Natalie J. Galant⁵  Lejla Pepic⁶  Paul Delgado-Olguin⁷  Kai Yu⁸  Kumaragurubaran Rathnakumar⁸  Faisal J. Alibhai⁸  Makon-Sébastien Njock⁸  Mansoor Husain⁸  M. Ahsan Siraj⁸  Ren-Ke Li⁸  Sneha Raju⁸  Zhiqi Chen⁸  Kathryn L. Howe⁹  Mark Chandy^1,10  Amalia Caballero^1,11  Kim A. Connelly^1,11  Carmina Anjelica Perez-Romero^1,11  Yaxu Wang^1,11  Lijun Chi^1,11 

[1] Department of Laboratory Medicine & Pathobiology, University of Toronto, Toronto, ON, Canada;Toronto General Hospital Research Institute, University Health Network, Toronto, ON, Canada;Department of Laboratory Medicine & Pathobiology, University of Toronto, Toronto, ON, Canada;Toronto General Hospital Research Institute, University Health Network, Toronto, ON, Canada;Peter Munk Cardiac Centre, University Health Network, Toronto, ON, Canada;Department of Medicine, Division of Cardiology, University of Colorado School of Medicine, Aurora, CO, USA;Keenan Biomedical Research Centre, Li Ka Shing Knowledge Institute, St. Michael’s Hospital, University of Toronto, Toronto, ON, Canada;Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada;Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA, USA;Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA, USA;Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada;Toronto General Hospital Research Institute, University Health Network, Toronto, ON, Canada;Toronto General Hospital Research Institute, University Health Network, Toronto, ON, Canada;Peter Munk Cardiac Centre, University Health Network, Toronto, ON, Canada;Toronto General Hospital Research Institute, University Health Network, Toronto, ON, Canada;Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA, USA;Translational Medicine, The Hospital for Sick Children, Toronto, ON, Canada;

关键词: Endothelial cell;    Microvasculature;    Diabetes;    Extracellular vesicle;    microRNA;    Biomarker;    Diastolic dysfunction;    Heart failure with preserved ejection fraction;   

DOI  :  10.1186/s12933-022-01458-z

来源: Springer

【 摘 要 】

BackgroundType 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.MethodsThe 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).ResultsWe 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.ConclusionsMiR-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.

【 授权许可】

CC BY