Mapping the cellular and molecular landscape of cardiac non-myocytes in murine diabetic cardiomyopathy
Charles D. Cohen,
Miles J. De Blasio,
Gabriella E. Farrugia,
Malathi S.I. Dona,
Ian Hsu,
Darnel Prakoso,
Helen Kiriazis,
Crisdion Krstevski,
David M. Nash,
Mandy Li,
Taylah L. Gaynor,
Minh Deo,
Grant R. Drummond,
Rebecca H. Ritchie,
Alexander R. Pinto
Affiliations
Charles D. Cohen
Cardiac Cellular Systems, Baker Heart and Diabetes Institute, Prahran, VIC, Australia; Heart Failure Pharmacology, Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Parkville, VIC, Australia; Department of Microbiology, Anatomy, Physiology and Pharmacology, La Trobe University, Bundoora, VIC, Australia; Centre for Cardiovascular Biology and Disease Research, La Trobe University, Melbourne, VIC, Australia
Miles J. De Blasio
Heart Failure Pharmacology, Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Parkville, VIC, Australia; Department of Pharmacology, Monash University, Clayton, VIC, Australia
Gabriella E. Farrugia
Cardiac Cellular Systems, Baker Heart and Diabetes Institute, Prahran, VIC, Australia; Baker Department of Cardiovascular Research and Implementation, La Trobe University, Melbourne, VIC, Australia
Malathi S.I. Dona
Cardiac Cellular Systems, Baker Heart and Diabetes Institute, Prahran, VIC, Australia
Ian Hsu
Cardiac Cellular Systems, Baker Heart and Diabetes Institute, Prahran, VIC, Australia
Darnel Prakoso
Heart Failure Pharmacology, Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Parkville, VIC, Australia
Helen Kiriazis
Preclinical Cardiology, Microsurgery and Imaging Platform, Baker Heart and Diabetes Institute, Prahran, VIC, Australia; Baker Department of Cardiometabolic Health, University of Melbourne, Parkville, VIC, Australia
Crisdion Krstevski
Cardiac Cellular Systems, Baker Heart and Diabetes Institute, Prahran, VIC, Australia; Department of Microbiology, Anatomy, Physiology and Pharmacology, La Trobe University, Bundoora, VIC, Australia; Centre for Cardiovascular Biology and Disease Research, La Trobe University, Melbourne, VIC, Australia
David M. Nash
Heart Failure Pharmacology, Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Parkville, VIC, Australia
Mandy Li
Heart Failure Pharmacology, Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Parkville, VIC, Australia
Taylah L. Gaynor
Cardiac Cellular Systems, Baker Heart and Diabetes Institute, Prahran, VIC, Australia; Department of Microbiology, Anatomy, Physiology and Pharmacology, La Trobe University, Bundoora, VIC, Australia; Centre for Cardiovascular Biology and Disease Research, La Trobe University, Melbourne, VIC, Australia
Minh Deo
Heart Failure Pharmacology, Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Parkville, VIC, Australia
Grant R. Drummond
Centre for Cardiovascular Biology and Disease Research, La Trobe University, Melbourne, VIC, Australia
Rebecca H. Ritchie
Heart Failure Pharmacology, Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Parkville, VIC, Australia; Department of Microbiology, Anatomy, Physiology and Pharmacology, La Trobe University, Bundoora, VIC, Australia; Centre for Cardiovascular Biology and Disease Research, La Trobe University, Melbourne, VIC, Australia; Corresponding author
Alexander R. Pinto
Cardiac Cellular Systems, Baker Heart and Diabetes Institute, Prahran, VIC, Australia; Department of Microbiology, Anatomy, Physiology and Pharmacology, La Trobe University, Bundoora, VIC, Australia; Centre for Cardiovascular Biology and Disease Research, La Trobe University, Melbourne, VIC, Australia; Baker Department of Cardiometabolic Health, University of Melbourne, Parkville, VIC, Australia; Corresponding author
Summary: Diabetes is associated with a significantly elevated risk of heart failure. However, despite extensive efforts to characterize the phenotype of the diabetic heart, the molecular and cellular protagonists that underpin cardiac pathological remodeling in diabetes remain unclear, with a notable paucity of data regarding the impact of diabetes on non-myocytes within the heart. Here we aimed to define key differences in cardiac non-myocytes between spontaneously type-2 diabetic (db/db) and healthy control (db/h) mouse hearts. Single-cell transcriptomic analysis revealed a concerted diabetes-induced cellular response contributing to cardiac remodeling. These included cell-specific activation of gene programs relating to fibroblast hyperplasia and cell migration, and dysregulation of pathways involving vascular homeostasis and protein folding. This work offers a new perspective for understanding the cellular mediators of diabetes-induced cardiac pathology, and pathways that may be targeted to address the cardiac complications associated with diabetes.
