Abstract Number: PB1260
Meeting: ISTH 2022 Congress
Background: Erythrocytes (red blood cells, RBCs) actively participate in the control of vascular nitric oxide (NO) bioavailability. Increased expression of arginase-1 (ARG1), an important regulator of NO production by competing with endothelial NO synthase (eNOS) for L-arginine, is seen in erythrocytes of patients at risk for vascular dysfunction. Our group has previously shown that atherosclerotic plaque bleeding and erythrocyte extravasation promote vascular calcification by mechanisms involving NO.
Aims: To determine the significance of ARG1 in murine erythrocytes for vascular smooth muscle cell (VSMC) NO signaling, osteoblastic differentiation and calcification.
Methods: Atherosclerosis-prone mice lacking ARG1 in RBCs (apoE-/- RBC.ARG1 knockout, KO) were generated by crossing erythropoietin Cre recombinase transgenic mice into the apolipoprotein E-deficient background followed by intercrosses with ARG1flox/flox transgenic mice and feeding Western type diet.
Results: Conditional deletion of ARG1 increased the erythrocyte NO content in an eNOS-dependent manner, without affecting erythrocyte numbers, morphology or removal in the spleen. Vascular calcification was significantly enhanced in apoE-/- RBC.ARG1 knockout mice, as shown by molecular imaging of osteogenic activity using OsteoSense™ and verified by Alizarin staining of calcium phosphate deposits on cross-sections through the aortic root. Incubation of VSMCs with lysed RBC membranes from apoE-/- RBC.ARG1-KO mice also accelerated osteoblastic differentiation in vitro, and calcium deposits and osteogenic marker mRNA levels decreased in the presence of a NO scavenger or inhibition of NO signaling. Increased expression of the protein denitrosylase GSNOR (S-nitrosoglutathione reductase), degradation of S-nitrosoglutathione to glutathione and reduced protein S-nitrosation of ARG1 were identified as mechanisms leading to VSMC calcification in mice lacking ARG1 in erythrocytes.
Conclusion(s): Our findings suggest an important role of erythrocyte ARG1 in the control of vascular L-arginine metabolism, NO bioactivity and signaling and identify GSNOR and protein S-denitrosation of ARG1 as potential target to prevent vascular smooth muscle cell calcification.
To cite this abstract in AMA style:Gogiraju R, Renner L, Bochenek M, Zifkos K, Molitor M, Wenzel P, Danckwardt S, Münzel T, Schäfer K. Importance of Erythrocyte Arginase-1 for Vascular Smooth Muscle Cell NO Signaling and Calcification [abstract]. https://abstracts.isth.org/abstract/importance-of-erythrocyte-arginase-1-for-vascular-smooth-muscle-cell-no-signaling-and-calcification/. Accessed October 1, 2023.
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