ADAMTS13 Deficiency Shortens the Life Span of Mice With Experimental Diabetes

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 mice made diabetic by streptozotocin, we investigated the impact of the lack of ADAMTS13 on the development of diabetes-associated end-organ complications. 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 mice exhibited an aberrant distribution of the ventricular gap junction connexin 43 and increased phosphorylation of Ca/calmodulin-dependent kinase II (CaMKII), and with the consequent CaMKII-induced disturbance in Ca 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.

Alteration of thyroid hormone signaling triggers the diabetes-induced pathological growth, remodeling, and dedifferentiation of podocytes

“…Tissues from BTBR wild-type and BTBR Lep ob/ob mice at 14 weeks of age, C57BL/6 wild-type mice injected intraperitoneally with saline or streptozotocin (200 mg/kg body weight, MilliporeSigma) as previously described (69), and 6-month-old Zucker diabetic fatty rats (ZDF/Gmi-fa/fa) and age-matched nondiabetic lean rats (ZDF/Gmi-fa/+) were used for immunohistochemical studies.…”

Sirt3 Deficiency Shortens Life Span and Impairs Cardiac Mitochondrial Function Rescued by Opa1 Gene Transfer

“…Heart rate and rhythm were simultaneously monitored by three-lead electrocardiogram (ECG). The cardiac function was evaluated at rest and at peak after intraperitoneal injection of a single bolus of dobutamine (1.5 lg/g of body weight), an established method for assessing the myocardial contractile reserve (10,48). Echocardiographic scans and ECG recordings were repeated immediately after a single bolus injection and then periodically over 10 min, until the peak heart rate response was reached and heart rate began to decline again.…”

CaMKII orchestrates endoplasmic reticulum stress and apoptosis in doxorubicin‐induced cardiotoxicity by regulating the IRE1α/XBP1s pathway

“… 47 In addition, there is evidence that the ADAMTS13‐TSP1 axis regulates CaMKII activation, which in turn is responsible for heart failure. 25 However, whether the IRE1α/XBP1s pathway is involved in the beneficial effects of CaMKII inhibition and the underlying mechanisms CaMKII activation in Dox‐induced cardiotoxicity are still to be elucidated. Consistently, our results showed that Dox significantly reduced IRE1α and XBP1s levels.…”

“…TSP1 is highly expressed in large vessels and in the myocardium in diabetic animals, and it has been shown to bind ADAMTS13 to form protein complexes. 25 , 26 However, the cellular mechanisms through which CaMKII regulates cardiac structure and function in Dox‐induced cardiotoxicity are less clear. In this study, we aimed to investigate whether ADAMTS13‐TSP1 could regulate CaMKII activation and whether CaMKII inhibition improved Dox‐induced cardiotoxicity by inhibiting ER stress by regulating the IRE1α/XBP1 pathway.…”

“…There is evidence that in cardiomyocytes, the ADAMTS13‐thrombospondin 1 (TSP1) axis regulates CaMKII phosphorylation, which in turn is responsible for heart failure. TSP1 is highly expressed in large vessels and in the myocardium in diabetic animals, and it has been shown to bind ADAMTS13 to form protein complexes 25,26 . However, the cellular mechanisms through which CaMKII regulates cardiac structure and function in Dox‐induced cardiotoxicity are less clear.…”