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Inhibition of calpain reduces oxidative stress and attenuates endothelial dysfunction in diabetes
- Source :
- Cardiovascular Diabetology
- Publication Year :
- 2014
- Publisher :
- Springer Science and Business Media LLC, 2014.
-
Abstract
- Aims The present study was to investigate the role of calpain in reactive oxygen species (ROS) production in endothelial cells and endothelium-dependent vascular dysfunction under experimental conditions of diabetes. Methods and results Exposure to high glucose activated calpain, induced apoptosis and reduced nitric oxide (NO) production without changing eNOS protein expression, its phosphorylation and dimers formation in primary human umbilical vein endothelial cells (HUVECs). These effects of high glucose correlated with intracellular ROS production and mitochondrial superoxide generation. Selectively scavenging mitochondrial superoxide increased NO production in high glucose-stimulated HUVECs. Inhibition of calpain using over-expression of calpastatin or pharmacological calpain inhibitor prevented high glucose-induced ROS production, mitochondrial superoxide generation and apoptosis, which were concurrent with an elevation of NO production in HUVECs. In mouse models of streptozotocin-induced type-1 diabetes and OVE26 type-1 diabetic mice, calpain activation correlated with an increase in ROS production and peroxynitrite formation in aortas. Transgenic over-expression of calpastatin reduced ROS production and peroxynitrite formation in diabetic mice. In parallel, diabetes-induced reduction of endothelium-dependent relaxation in aortic ring was reversed by over-expression of calpastatin in mouse models of diabetes. However, the protective effect of calpastatin on endothelium-dependent relaxation was abrogated by eNOS deletion in diabetic mice. Conclusions This study suggests that calpain may play a role in vascular endothelial cell ROS production and endothelium-dependent dysfunction in diabetes. Thus, calpain may be an important therapeutic target to overcome diabetes-induced vascular dysfunction.
- Subjects :
- Male
medicine.medical_specialty
Endothelium
Endocrinology, Diabetes and Metabolism
Mice, Transgenic
medicine.disease_cause
Mice
chemistry.chemical_compound
Organ Culture Techniques
Internal medicine
Diabetes Mellitus
Human Umbilical Vein Endothelial Cells
medicine
Animals
Humans
Endothelial dysfunction
Glycoproteins
Original Investigation
Calpastatin
chemistry.chemical_classification
Reactive oxygen species
biology
Calpain
business.industry
Diabetes
ROS
medicine.disease
Mice, Inbred C57BL
Oxidative Stress
medicine.anatomical_structure
Endocrinology
chemistry
Apoptosis
eNOS
biology.protein
Endothelium, Vascular
Reactive Oxygen Species
Cardiology and Cardiovascular Medicine
business
Peroxynitrite
Oxidative stress
Subjects
Details
- ISSN :
- 14752840
- Volume :
- 13
- Database :
- OpenAIRE
- Journal :
- Cardiovascular Diabetology
- Accession number :
- edsair.doi.dedup.....de85470bda80a3eb830fc9ddd125c3f9