ADAMTS13 Deficiency Shortens the Life Span of Mice With Experimental Diabetes

Paola Cassis, Domenico Cerullo, Cristina Zanchi, Daniela Corna, Vincenzo Lionetti, Fabrizio Giordano, Rubina Novelli, Sara Conti, Valentina Casieri, Marco Matteucci, Monica Locatelli, Giulia Taraboletti, Sebastian Villa, Sara Gastoldi, Giuseppe Remuzzi, Ariela Benigni, Carlamaria Zoja

Research output: Contribution to journalArticle

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.

Original languageEnglish
Pages (from-to)2069-2083
Number of pages15
JournalDiabetes
Volume67
Issue number10
DOIs
Publication statusPublished - Oct 1 2018

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

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    Cassis, P., Cerullo, D., Zanchi, C., Corna, D., Lionetti, V., Giordano, F., Novelli, R., Conti, S., Casieri, V., Matteucci, M., Locatelli, M., Taraboletti, G., Villa, S., Gastoldi, S., Remuzzi, G., Benigni, A., & Zoja, C. (2018). ADAMTS13 Deficiency Shortens the Life Span of Mice With Experimental Diabetes. Diabetes, 67(10), 2069-2083. https://doi.org/10.2337/db17-1508