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ADAMTS13 Deficiency Shortens the Life Span of Mice With Experimental Diabetes
- Source :
- Diabetes. 67(10)
- Publication Year :
- 2017
-
Abstract
- In patients with diabetes, impaired activity of ADAMTS13 (a disintegrin and metalloprotease with thrombospondin type 1 repeats, member 13), the plasma metalloprotease that cleaves highly thrombogenic von Willebrand factor multimers, is a major risk factor of cardiovascular events. Here, using Adamts13−/− mice made diabetic by streptozotocin, we investigated the impact of the lack of ADAMTS13 on the development of diabetes-associated end-organ complications. Adamts13−/− mice experienced a shorter life span than their diabetic wild-type littermates. It was surprising that animal death was not related to the occurrence of detectable thrombotic events. The lack of ADAMTS13 drastically increased the propensity for ventricular arrhythmias during dobutamine-induced stress in diabetic mice. Cardiomyocytes of diabetic Adamts13−/− mice exhibited an aberrant distribution of the ventricular gap junction connexin 43 and increased phosphorylation of Ca2+/calmodulin-dependent kinase II (CaMKII), and with the consequent CaMKII-induced disturbance in Ca2+ handling, which underlie propensity for arrhythmia. In vitro, thrombospondin 1 (TSP1) promoted, in a paracrine manner, CaMKII phosphorylation in murine HL-1 cardiomyocytes, and ADAMTS13 acted to inhibit TSP1-induced CaMKII activation. In conclusion, the deficiency of ADAMTS13 may underlie the onset of lethal arrhythmias in diabetes through increased CaMKII phosphorylation in cardiomyocytes. Our findings disclose a novel function for ADAMTS13 beyond its antithrombotic activity.
- Subjects :
- 0301 basic medicine
Male
medicine.medical_specialty
Endocrinology, Diabetes and Metabolism
Connexin
ADAMTS13 Protein
030204 cardiovascular system & hematology
Diabetes Mellitus, Experimental
Thrombospondin 1
03 medical and health sciences
Mice
0302 clinical medicine
hemic and lymphatic diseases
Diabetes mellitus
Ca2+/calmodulin-dependent protein kinase
Internal medicine
Dobutamine
Internal Medicine
medicine
Animals
Phosphorylation
Mice, Knockout
Thrombospondin
business.industry
Reverse Transcriptase Polymerase Chain Reaction
Streptozotocin
medicine.disease
Immunohistochemistry
ADAMTS13
030104 developmental biology
Endocrinology
Connexin 43
cardiovascular system
business
Calcium-Calmodulin-Dependent Protein Kinase Type 2
Shear Strength
medicine.drug
Subjects
Details
- ISSN :
- 1939327X
- Volume :
- 67
- Issue :
- 10
- Database :
- OpenAIRE
- Journal :
- Diabetes
- Accession number :
- edsair.doi.dedup.....8efff5083a06c51edcdd683659ab1be7