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- Title
12(S)-HETE mediates diabetes-induced endothelial dysfunction by activating intracellular endothelial cell TRPV1.
- Authors
Otto, Mandy; Bucher, Clarissa; Wantao Liu; Müller, Melanie; Schmidt, Tobias; Kardell, Marina; Driessen, Marvin Noel; Rossaint, Jan; Gross, Eric R.; Wagner, Nana-Maria; Liu, Wantao
- Abstract
Patients with diabetes develop endothelial dysfunction shortly after diabetes onset that progresses to vascular disease underlying the majority of diabetes-associated comorbidities. Increased lipid peroxidation, mitochondrial calcium overload, and mitochondrial dysfunction are characteristics of dysfunctional endothelial cells in diabetic patients. We here identified that targeting the lipid peroxidation product 12(S)-hydroxyeicosatetraenoic acid-induced [12(S)-HETE-induced] activation of the intracellularly located cation channel transient receptor potential vanilloid 1 (TRPV1) in endothelial cells is a means to causally control early-stage vascular disease in type I diabetic mice. Mice with an inducible, endothelium-specific 12/15-lipoxygenase (12/15Lo) knockout were protected similarly to TRPV1-knockout mice from type 1 diabetes-induced endothelial dysfunction and impaired vascular regeneration following arterial injury. Both 12(S)-HETE in concentrations found in diabetic patients and TRPV1 agonists triggered mitochondrial calcium influx and mitochondrial dysfunction in endothelial cells, and 12(S)-HETE effects were absent in endothelial cells from TRPV1-knockout mice. As a therapeutic consequence, we found that a peptide targeting 12(S)-HETE-induced TRPV1 interaction at the TRPV1 TRP box ameliorated diabetes-induced endothelial dysfunction and augmented vascular regeneration in diabetic mice. Our findings suggest that pharmacological targeting of increased endothelial lipid peroxidation can attenuate diabetes-induced comorbidities related to vascular disease.
- Subjects
ENDOTHELIUM diseases; ENDOTHELIAL cells; TRPV cation channels; TRP channels; PEOPLE with diabetes; ANIMAL experimentation; ARACHIDONIC acid; CARRIER proteins; CELLULAR signal transduction; COMPARATIVE studies; DIABETES; DIABETIC angiopathies; ENDOTHELIUM; EPITHELIAL cells; TYPE 1 diabetes; RESEARCH methodology; MEDICAL cooperation; MICE; RESEARCH; EVALUATION research
- Publication
Journal of Clinical Investigation, 2020, Vol 130, Issue 9, p4999
- ISSN
0021-9738
- Publication type
journal article
- DOI
10.1172/JCI136621