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 VWF 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. We found that Adamts13-/- mice experienced shortened lifespan with their wild-type diabetic littermates. Surprisingly,animal death was not related to the occurrence of detectable thrombotic events. The lack of ADAMTS13 drastically increased the propensity to ventricular arrhythmias during dobutamine stress in diabetic mice. Cardiomyocytes of Adamts13-/- diabetic mice,exhibited an aberrant distribution of the ventricular gap junction connexin 43 (Cx43), increased phosphorylation of Ca2+/calmodulin-dependent kinase II (CaMKII) and consequent CaMKII-induced disturbance in Ca2+ handling, which underlie arrhythmia propensity. In vitro, thrombospondin1 (TSP1) promoted in a paracrine manner CaMKII phosphorylation in murine HL-1 cardiomyocytes and ADAMTS13 acted as an inhibitory factor for 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 the antithrombotic activity.
|Titolo:||ADAMTS13 deficiency shortens the lifespan of mice with experimental diabetes|
|Data di pubblicazione:||2018|
|Appare nelle tipologie:||1.1 Articolo su Rivista/Article|