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Pathologic properties of SOD3 variant R213G in the cardiovascular system through the altered neutrophils function.

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.

SUBMITTER: Kwon MJ

PROVIDER: S-EPMC6994104 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Pathologic properties of SOD3 variant R213G in the cardiovascular system through the altered neutrophils function.

Kwon Myung-Ja MJ Lee Kyo-Young KY Ham Won-Gug WG Tak Lee-Jung LJ Agrahari Gaurav G Kim Tae-Yoon TY

PloS one 20200131 1

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 in ...[more]

PMID: 32004354

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Project description:Among 1299 older adults with 24-h Holter monitoring data at baseline, followed for approximately 15 years, 190 incident hip fractures occurred. Increased heart rate variability was independently associated with reduced risk of hip fracture among female participants.PurposeAutonomic nervous system function modulates bone remodeling in rodent osteoporosis models. We tested whether cardiovascular autonomic function is associated with hip fracture risk in humans.MethodsParticipants were 1299 subjects from the Cardiovascular Health Study (mean age 72.8 years). Eight heart rate variability (HRV) measures (time and frequency domains, detrended fluctuation analysis variables, and heart rate turbulence) were derived from 24-h Holter monitor scans in sinus rhythm. Median follow-up for incident hip fracture was 14.7 years [IQR 9.1, 20.2]. Cox proportional hazards models were used to calculate hazard ratios (95% confidence intervals, CI).ResultsThere were 144 hip fractures among 714 women (1.31 [1.06, 1.61] per 100-person years) and 46 among 585 men (0.62 [0.43, 0.90] per 100 person-years). From among HRV variables examined, a one standard deviation (SD) higher variation between normal heart beats over 24 h (the SD of NN intervals [SDNN]) was associated with a multivariable-adjusted lower hip fracture risk (HR [Formula: see text] 0.80; 95% CI 0.65-0.99; p = 0.04) in women. The adjusted association between very low frequency power, and hip fracture was borderline statistically significant in women (HR [Formula: see text] 0.82; 95% CI, 0.66-1.00; p = 0.06). When the 8 HRV variables were considered conjointly and adjusted for each other's association with hip fracture risk, a 1 SD higher SDNN value was significantly associated with reduced hip fracture risk in women (HR 0.74; 95% CI, 0.50-0.99; p = 0.05). No HRV variables were associated with hip fracture in men.ConclusionsIn older women, increased heart rate variation is associated with hip fracture risk.

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Pathologic properties of SOD3 variant R213G in the cardiovascular system through the altered neutrophils function.

Publications

Pathologic properties of SOD3 variant R213G in the cardiovascular system through the altered neutrophils function.

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