JACC: Basic to Translational Science (Dec 2019)
CFTR Therapeutics Normalize Cerebral Perfusion Deficits in Mouse Models of Heart Failure and Subarachnoid Hemorrhage
- Darcy Lidington, PhD,
- Jessica C. Fares, MSc,
- Franziska E. Uhl, PhD,
- Danny D. Dinh, MSc,
- Jeffrey T. Kroetsch, PhD,
- Meghan Sauvé, PhD,
- Firhan A. Malik, PhD,
- Frank Matthes, PhD,
- Lotte Vanherle, MSc,
- Arman Adel, BSc,
- Abdul Momen, MD, PhD,
- Hangjun Zhang, MD,
- Roozbeh Aschar-Sobbi, PhD,
- Warren D. Foltz, PhD,
- Hoyee Wan, BSc,
- Manabu Sumiyoshi, MD,
- R. Loch Macdonald, MD, PhD,
- Mansoor Husain, MD,
- Peter H. Backx, PhD, DVM,
- Scott P. Heximer, PhD,
- Anja Meissner, PhD,
- Steffen-Sebastian Bolz, MD, PhD
Affiliations
- Darcy Lidington, PhD
- Department of Physiology, University of Toronto, Toronto, Ontario, Canada; Toronto Centre for Microvascular Medicine at The Ted Rogers Centre for Heart Research Translational Biology and Engineering Program, University of Toronto, Ontario, Canada
- Jessica C. Fares, MSc
- Department of Physiology, University of Toronto, Toronto, Ontario, Canada; Toronto Centre for Microvascular Medicine at The Ted Rogers Centre for Heart Research Translational Biology and Engineering Program, University of Toronto, Ontario, Canada
- Franziska E. Uhl, PhD
- Wallenberg Center for Molecular Medicine and Department of Experimental Medical Science, Lund University, Lund, Sweden
- Danny D. Dinh, MSc
- Department of Physiology, University of Toronto, Toronto, Ontario, Canada; Toronto Centre for Microvascular Medicine at The Ted Rogers Centre for Heart Research Translational Biology and Engineering Program, University of Toronto, Ontario, Canada
- Jeffrey T. Kroetsch, PhD
- Department of Physiology, University of Toronto, Toronto, Ontario, Canada; Toronto Centre for Microvascular Medicine at The Ted Rogers Centre for Heart Research Translational Biology and Engineering Program, University of Toronto, Ontario, Canada
- Meghan Sauvé, PhD
- Department of Physiology, University of Toronto, Toronto, Ontario, Canada; Toronto Centre for Microvascular Medicine at The Ted Rogers Centre for Heart Research Translational Biology and Engineering Program, University of Toronto, Ontario, Canada
- Firhan A. Malik, PhD
- Department of Physiology, University of Toronto, Toronto, Ontario, Canada
- Frank Matthes, PhD
- Wallenberg Center for Molecular Medicine and Department of Experimental Medical Science, Lund University, Lund, Sweden
- Lotte Vanherle, MSc
- Wallenberg Center for Molecular Medicine and Department of Experimental Medical Science, Lund University, Lund, Sweden
- Arman Adel, BSc
- Department of Physiology, University of Toronto, Toronto, Ontario, Canada
- Abdul Momen, MD, PhD
- Division of Cell & Molecular Biology, Toronto General Hospital Research Institute, Toronto, Ontario, Canada
- Hangjun Zhang, MD
- Department of Physiology, University of Toronto, Toronto, Ontario, Canada; Toronto Centre for Microvascular Medicine at The Ted Rogers Centre for Heart Research Translational Biology and Engineering Program, University of Toronto, Ontario, Canada
- Roozbeh Aschar-Sobbi, PhD
- Division of Cardiology, University Health Network, Toronto, Ontario, Canada
- Warren D. Foltz, PhD
- STTARR Innovation Centre, Department of Radiation Oncology, Princess Margaret Hospital, Toronto, Ontario, Canada
- Hoyee Wan, BSc
- Labatt Family Centre of Excellence in Brain Injury and Trauma Research, Keenan Research Centre for Biomedical Research and Li Ka Shing Knowledge Institute, St. Michael’s Hospital, Toronto, Ontario, Canada; Division of Neurosurgery, St. Michael’s Hospital, and Department of Surgery, University of Toronto, Toronto, Ontario, Canada; Sunnybrook Research Institute, Physical Sciences Platform and Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada
- Manabu Sumiyoshi, MD
- Division of Neurosurgery, St. Michael’s Hospital, and Department of Surgery, University of Toronto, Toronto, Ontario, Canada; Institute of Health Biosciences, Department of Neurosurgery, University of Tokushima Graduate School, Tokushima, Japan
- R. Loch Macdonald, MD, PhD
- Labatt Family Centre of Excellence in Brain Injury and Trauma Research, Keenan Research Centre for Biomedical Research and Li Ka Shing Knowledge Institute, St. Michael’s Hospital, Toronto, Ontario, Canada; Division of Neurosurgery, St. Michael’s Hospital, and Department of Surgery, University of Toronto, Toronto, Ontario, Canada
- Mansoor Husain, MD
- Department of Physiology, University of Toronto, Toronto, Ontario, Canada; Division of Cell & Molecular Biology, Toronto General Hospital Research Institute, Toronto, Ontario, Canada; Heart & Stroke/Richard Lewar Centre of Excellence for Cardiovascular Research, University of Toronto, Toronto, Ontario, Canada; Department of Medicine, University of Toronto, Toronto, Ontario, Canada
- Peter H. Backx, PhD, DVM
- Division of Cardiology, University Health Network, Toronto, Ontario, Canada; Department of Biology, York University, Toronto, Ontario, Canada
- Scott P. Heximer, PhD
- Department of Physiology, University of Toronto, Toronto, Ontario, Canada; Heart & Stroke/Richard Lewar Centre of Excellence for Cardiovascular Research, University of Toronto, Toronto, Ontario, Canada
- Anja Meissner, PhD
- Department of Physiology, University of Toronto, Toronto, Ontario, Canada; Wallenberg Center for Molecular Medicine and Department of Experimental Medical Science, Lund University, Lund, Sweden
- Steffen-Sebastian Bolz, MD, PhD
- Department of Physiology, University of Toronto, Toronto, Ontario, Canada; Toronto Centre for Microvascular Medicine at The Ted Rogers Centre for Heart Research Translational Biology and Engineering Program, University of Toronto, Ontario, Canada; Heart & Stroke/Richard Lewar Centre of Excellence for Cardiovascular Research, University of Toronto, Toronto, Ontario, Canada; Address for correspondence: Dr. Steffen-Sebastian Bolz, Toronto Centre for Microvascular Medicine at TBEP, University of Toronto, 661 University Avenue, 14th Floor, Toronto, Ontario, Canada, M5G 1M1.
- Journal volume & issue
-
Vol. 4,
no. 8
pp. 940 – 958
Abstract
Summary: Heart failure (HF) and subarachnoid hemorrhage (SAH) chronically reduce cerebral perfusion, which negatively affects clinical outcome. This work demonstrates a strong relationship between cerebral artery cystic fibrosis transmembrane conductance regulator (CFTR) expression and altered cerebrovascular reactivity in HF and SAH. In HF and SAH, CFTR corrector compounds (C18 or lumacaftor) normalize pathological alterations in cerebral artery CFTR expression, vascular reactivity, and cerebral perfusion, without affecting systemic hemodynamic parameters. This normalization correlates with reduced neuronal injury. Therefore, CFTR therapeutics have emerged as valuable clinical tools to manage cerebrovascular dysfunction, impaired cerebral perfusion, and neuronal injury. Key Words: cognitive impairment, corrector compounds, cystic fibrosis transmembrane conductance regulator (CFTR), myogenic vasoconstriction, sphingosine-1-phosphate, tumor necrosis factor, vascular smooth muscle cells
