Abstract
The SOD3 variant, SOD3R213G, results from substitution of arginine to glycine at amino acid 213 (R213G) in its heparin binding domain (HBD) and is a common genetic variant, reported to be associated with ischemic heart disease. However, little is understood about the role of SOD3R213G in innate immune function, and how it leads to dysfunction of the cardiovascular system. We observed pathologic changes in SOD3R213G transgenic (Tg) mice, including cystic medial degeneration of the aorta, heart inflammation, and increased circulating and organ infiltrating neutrophils. Interestingly, SOD3R213G altered the profile of SOD3 interacting proteins in neutrophils in response to G-CSF. Unexpectedly, we found that G-CSF mediated tyrosine phosphatase, SH-PTP1 was down-regulated in the neutrophils of SOD3R213G overexpressing mice. These effects were recovered by reconstitution with Wt SOD3 expressing bone marrow cells. Overall, our study reveals that SOD3R213G plays a crucial role in the function of the cardiovascular system by controlling innate immune response and signaling. These results suggest that reconstitution with SOD3 expressing bone marrow cells may be a therapeutic strategy to treat SOD3R213G mediated diseases.
Highlights
Superoxide dismutase 3 (SOD3) is a member of the SOD family that scavenges superoxide and ROS produced by cells and tissues during inflammation [1]
SOD3R213G alters the function of neutrophils gene expression was measured by qRT-PCR
We demonstrated that overexpression of SOD3R213G causes aortic degeneration and heart inflammation, which eventually leads to loss in cardiovascular function
Summary
Superoxide dismutase 3 (SOD3) is a member of the SOD family that scavenges superoxide and ROS produced by cells and tissues during inflammation [1]. SOD3 is a glycoprotein with a heparin-binding domain (HBD) and is distributed throughout the extracellular matrix (ECM) of many tissues, including blood vessels and heart [2,3,4,5,6]. Binding of the HBD to heparan sulfate proteoglycans on cell surfaces and ECM is critical for the function of SOD3 [4], protecting these organs against oxidative stress [4, 7, 8]. Considering that the ECM is essential for regulating intercellular communication [11], SOD3 may play a critical role for maintaining proper cellular function
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