Arginase-1 Deletion in Erythrocytes Promotes Vascular Calcification via Enhanced GSNOR (S-Nitrosoglutathione Reductase) Expression and NO Signaling in Smooth Muscle Cells

Abstract

BACKGROUND: Erythrocytes (red blood cells) participate in the control of vascular NO bioavailability. The purpose of this study was to determine whether and how genetic deletion of ARG1 (arginase-1) affects vascular smooth muscle cell NO signaling, osteoblastic differentiation, and atherosclerotic lesion calcification. METHODS: Atherosclerosis-prone mice with conditional, erythrocyte-restricted deletion of ARG1 (apoE −/− red blood cell.ARG1 knockout) were generated and vascular calcification studied using molecular imaging of the osteogenic activity agent OsteoSense, Alizarin staining or immunohistochemistry, qPCR of osteogenic markers and ex vivo assays. RESULTS: Atherosclerotic lesion size at the aortic root did not differ, but calcification was significantly more pronounced in apoE −/− mice lacking erythrocyte ARG1. Incubation of murine and human VSMCs with lysed erythrocyte membranes from apoE −/− red blood cell. ARG1-knockout mice accelerated their osteogenic differentiation, and mRNA transcripts of osteogenic markers decreased following NO scavenging. In addition to NO signaling via sGC (soluble guanylyl cyclase), overexpression of GSNOR (S-nitrosoglutathione reductase) enhanced degradation of S-nitrosoglutathione to glutathione and reduced protein S-nitrosation of HSP (heat shock protein)-70 were identified as potential mechanisms of vascular smooth muscle cell calcification in mice lacking ARG1 in erythrocytes, and calcium phosphate deposition was enhanced by heat shock and prevented by GSNOR inhibition. Messenger RNA levels of enzymes metabolizing the arginase products L-ornithine and L-proline also were elevated in VSMCs, paralleled by increased proliferation, myofibroblast marker and collagen type 1 expression. CONCLUSIONS: Our findings support an important role of erythrocyte ARG1 for NO bioavailability and L-arginine metabolism in VSMCs, which controls atherosclerotic lesion composition and calcification.

Unveiling the metabolic and coagulation disruptions in SARS‐CoV‐2‐associated acute macular neuroretinopathy: A case–control study

“…Experimental models have demonstrated that inhibiting or eliminating ARG1 can reinstate endothelial function by enhancing bioavailability 39 . Additionally, researchers have noted that ARG1 stimulates collagen synthesis in SMCs by channeling arginine metabolism toward proline, stimulating SMC proliferation, migration, and collagen deposition, thereby fostering vascular fibrosis and stiffness that ultimately underlie vascular occlusion 40 . In this context, the study corroborated elevated levels of both ARG1 and l ‐proline in the serum of AMN‐SARS‐CoV‐2 patients, suggesting the activation of the ARG1‐associated arginine metabolism and collagen synthesis pathways within the AMN‐SARS‐CoV‐2 milieu, suggesting ARG1 represents a promising therapeutic target for AMN‐SARS‐CoV‐2.…”

Unveiling the Metabolic and Coagulation Disruptions in SARS-CoV-2-Associated Acute Macular Neuroretinopathy: A Case-control Study

“…Experimental models have demonstrated that inhibiting or eliminating ARG1 can reinstate endothelial function by enhancing bioavailability [34]. Additionally, researchers have noted that ARG1 stimulates collagen synthesis in smooth muscle cells (SMCs) by channeling arginine metabolism toward proline, stimulating SMC proliferation, migration, and collagen deposition, thereby fostering vascular fibrosis and stiffness that ultimately underlie vascular occlusion [35]. In this context, the study corroborated elevated levels of both ARG1 and L-proline in the serum of AMN-SARS-CoV-2 patients, suggesting the activation of the ARG1-associated arginine metabolism and collagen synthesis pathways within the AMN-SARS-CoV-2 milieu, suggesting ARG1 represents a promising therapeutic target for AMN-SARS-CoV-2.…”

The renal artery-aorta angle associated with renal artery plaque: a retrospective analysis based on CT

“…The above outcome is correspond with the conclusions of Tafuri et al [ 33 ]. The proximal segment is the most vulnerable to suffer the impact of blood flow velocity and fluid shear stress (FSS), and the vascular intima is damaged more easily, vascular smooth muscle cells are prone to differentiate into an osteoblast/chondrocyte phenotype, where inflammatory mediators, recruitment of activated macrophages, lipids and inflammatory factors are more likely to release and deposit [ 34 ]. The above factors are conducive to provoke and regulate the pathological process of plaque.…”