ADAM17 mediates TNF release from pericardial adipose tissue arteries to remotely impair coronary dilation in patients with type 2 diabetes (1071.5)

Abstract

Pericardial adipose tissue (PAT) is a major source of pro‐inflammatory cytokine TNF, which contributes to the development coronary microvascular dysfunction in type 2 diabetes (T2DM). We hypothesized that TNF is actively cleaved from arteries of PAT by the sheddase, ADAM17 to alter the function of coronary resistance arteries (CRA) in T2DM. Arterioles were dissected from PAT (PATA) and also from the right atrial appendages obtained at the time of cardiac surgery of patients. PATAs and CRA were cannulated and serially connected and changes in CRA diameter were measured with video microscopy. The endothelium‐dependent vasodilator, bradykinin elicited substantial dilation in T2DM CRA, which was significantly reduced when the CRA connected to PATA from T2DM but not from nonDM PATA. Incubation of PATA with soluble TNF receptor, TNF receptor functional blocking antibody or inhibitor of ADAM17, all restored bradykinin‐induced dilation of CRA to the control level. We found an abundant expression of ADAM17 in the endothelium of PATA in both T2DM and nonDM patients. Despite no differences in the level of ADAM17 protein expression, a significantly increased ADAM17 activity was measured in PATA of T2DM patients. We conclude that PATA from T2DM patients are an important source of circulating TNF that can remotely impair dilation of CRA and may contribute to the pathogenesis of coronary microvascular disease in DM.Grant Funding Source: NIH HL104126