Treatment with the ADAM17 sheddase inhibitor, phosphatidylserine, improves endothelial function and reduces arterial stiffness in diabetic mice

Abstract

Patients with type 2 diabetes (T2D) have an increased incidence of cardiovascular disease (CVD) morbidity and mortality. Indeed, CVD is the primary cause of death in T2D. Arterial stiffness and hypertension are both implicated in the progression of CVD in T2D. Moreover, arterial stiffening is posited to precede the development of hypertension and is associated with a higher risk for incidence of T2D. We propose that a central mediator of these pathologies is the aberrant upregulation of protein sheddase(s) that damage mechanosenstive structures in the endothelium leading to endothelial dysfunction and subsequent increased arterial stiffness. We have previously demonstrated that the sheddase/metallopeptidase, a disintegrin and matrix metalloproteinase (ADAM17), is upregulated in the vascular endothelium of patients with T2D, while others have shown that exogenous phosphatidylserine (PS) can work as a competitive inhibitor of ADAM17 sheddase activity. Therefore, we hypothesized that inhibition of ADAM17 with PS would ameliorate endothelial dysfunction in a mouse model of T2D (db/db) by improving endothelial mechanosensation, and that this effect would be associated with reductions in blood pressure and arterial stiffness. We tested this hypothesis in 20 db/db male mice aged 9 weeks that were randomized to receive a daily peanut butter pellet as vehicle control or the pellet with PS (200 mg/kg/day) for 28 days. A third group of 10 wild-type C57/Bl6 male mice served as untreated controls. All reported differences are significant at P<0.05. Compared with wild-types, db/db control mice had elevated systolic blood pressure and pulse wave velocity, whereas PS treatment reduced both when compared with db/db controls. Excised mesenteric arteries were assessed for vasodilatory responses using pressure myography and db/db control mice showed impaired flow-mediated dilation (FMD) compared to wild-types. FMD was restored in PS-treated db/db mice. Aortas, femoral and mesenteric arteries were assessed for mechanical and structural characteristics. All of these arteries displayed increased incremental modulus of elasticity (increased stiffness) in db/db control mice compared with wilt-types. PS treatment reduced arterial stiffness across arteries in db/db mice. Our findings indicate that PS treatment improves endothelial function and reduces arterial stiffness in diabetic mice and suggest that PS may be a beneficial therapeutic approach to improve overall vascular function in the setting of T2D. R01HL151384 (to LAML and JP) and R01HL153264 (to LAML and JP) This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.