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Published on: February 25, 2016
Reactive oxygen species-selective regulation of aortic inflammatory gene expression in Type 2 diabetes
Alejandra San Martín1, Pingfeng Du, Anna Dikalova
1Division of Cardiology, Department of Medicine, Emory University, 1639 Pierce Dr., Atlanta, GA 30322, USA.
Abstract:
Vascular diseases are a major complication of diabetes mellitus (DM), although their etiology is poorly understood. NADPH oxidase-derived reactive oxygen species (ROS) production and inflammation are potential mediators of DM-associated vascular diseases. Using db/db mice as a Type 2 diabetes model, we examined the relationship between NADPH oxidase-derived ROS and vascular inflammation. When compared with control m+/+ mice, aortas from 4- and 12-wk-old db/db mice had higher NADPH oxidase activity and increased superoxide levels, leading to NADPH oxidase-dependent impaired vasodilation at 12 wk. Diabetes progression from 4 to 12 wk led to increased Nox1, Nox4, and p22(phox) subunit mRNAs and induced the expression of a group of matrix remodeling-related cytokines: connective tissue growth factor (CTGF), bone morphogenetic protein 4 (BMP-4), and osteopontin (OPN). After 8 wk of treatment with the superoxide scavenger Tempol, 12-wk-old db/db mice had lower superoxide production, reduced plasma glucose and lipids, and lower BMP-4 and OPN protein expression when compared with nontreated mice. No changes were observed with Tempol in CTGF or m+/+ mice. The ability of Tempol to reverse ROS production as well as OPN and BMP-4, but not CTGF, induction suggests that DM-induced vascular inflammation involves both ROS-sensitive and -insensitive pathways.
Insights
Diabetes-associated vascular inflammation involves reactive oxygen species (ROS) and inflammation. A study in mice showed that blocking ROS reduced vascular inflammation and improved blood vessel function, suggesting targeted therapies.
Area of Science:
- Cardiovascular Biology
- Endocrinology
- Oxidative Stress Research
Background:
- Vascular diseases are a significant complication of diabetes mellitus (DM), with unclear underlying mechanisms.
- NADPH oxidase-derived reactive oxygen species (ROS) and inflammation are implicated in diabetic vascular complications.
Purpose of the Study:
- To investigate the link between NADPH oxidase-derived ROS and vascular inflammation in a mouse model of Type 2 diabetes.
- To evaluate the therapeutic potential of a ROS scavenger in mitigating diabetes-induced vascular changes.
Main Methods:
- Utilized db/db mice as a model for Type 2 diabetes.
- Assessed NADPH oxidase activity, superoxide levels, and vasodilation in mouse aortas.
- Quantified mRNA and protein expression of matrix remodeling factors (CTGF, BMP-4, OPN).
- Administered Tempol, a superoxide scavenger, to diabetic mice and analyzed its effects.
Main Results:
- Diabetic db/db mice exhibited increased NADPH oxidase activity, superoxide levels, and impaired vasodilation compared to controls.
- Diabetes progression elevated specific NADPH oxidase subunit mRNAs (Nox1, Nox4, p22phox) and induced CTGF, BMP-4, and OPN.
- Tempol treatment reduced superoxide production, improved glycemic and lipid profiles, and decreased BMP-4 and OPN expression in diabetic mice.
Conclusions:
- NADPH oxidase-derived ROS contribute significantly to vascular dysfunction and inflammation in diabetes.
- Tempol's ability to reverse ROS production and specific inflammatory markers suggests a dual pathway (ROS-sensitive and -insensitive) in diabetic vascular disease.
- Targeting ROS may offer a therapeutic strategy for managing vascular complications in diabetes.
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