Increased Superoxide and Vascular Dysfunction in CuZnSOD-Deficient Mice

Didion, Sean P.; Ryan, Michael J.; Didion, Lisa; Fegan, Pamela E.; Sigmund, Curt D.; Faraci, Frank M.

doi:10.1161/01.res.0000043280.65241.04

Cited by 211 publications

(213 citation statements)

References 63 publications

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“…In both large arteries and microvessels, deficiency in Cu/Zn-SOD results in increased levels of vascular superoxide and peroxynitrite, increased myogenic tone, augmented vasoconstrictor responses, and impaired endothelium-dependent NO-mediated relaxation. 59,84,85 In the current study, we confirmed by Western blot analyses and immunohistochemical labeling significantly lower levels of Cu/Zn-SOD isoform expression in 24-mo-old compared to 9-mo-old MLV; such changes may be a contributor to the aging-associated impaired endothelium-dependent NO-mediated regulation on the lymphatic vessels. 4,24,30 While we did observe an increase EC-SOD isoform expression in 24-mo-old compared to 9-mo-old MLV via Western blot, we were not able to see any difference in expression of EC-SOD via immunohistochemical labeling.…”

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confidence: 79%

“…Studies suggest that inactivation of nitric oxide by superoxide contributes to impaired vascular function. [57][58][59][60] NO reacts with superoxide radical (O 2 -) to form peroxynitrite (ONOO -), which can further induce protein modification and DNA damage in the microvascular system. 61 Thus, decrease in NO bioavailability as a result of excess O 2 -formation is a major cause of endothelial dysfunction in aging.…”

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confidence: 99%

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Aged Lymphatic Contractility: Recent Answers and New Questions

Gashev

Chatterjee

2013

Lymphatic Research and Biology

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An overview is presented of recent findings related to biology of aging of the lymph transport system. The authors discuss recently obtained data on the aging-associated alterations of lymphatic contractility in thoracic duct and mesenteric lymphatic vessels; on comparisons of function of aged mesenteric lymphatic vessels in situ versus isolated specimens and important conclusions which arose from these studies; on aging-associated changes in functional status of mast cells located close to aged mesenteric lymphatic vessels; on evidence of presence of oxidative stress in aged lymphatic vessels and changes in arrangement of muscle cells in their walls. The authors conclude that future continuation of the research efforts in this area is necessary and will be able to provide not only novel fundamental knowledge on the biology of lymphatic aging, but also will create solid foundation for the subsequent developments of lymphatic-oriented therapeutic interventions in many diseases of the elderly.T he major task of the lymphatic system is lymph transport. This system of initial capillaries, transporting vessels, and nodes is designed to transport fluid, soluble molecules, and immune cells from the interstitium through the lymph nodes to the central veins. This system also provides the transportation route for inflammatory mediators, the products of tissue injury/destruction, foreign substances, and tumor cells. Dysfunctional lymph transport can result in a wide range of disturbances, including edema, altered immune cell trafficking, depressed immune function, and impaired lipid metabolism. The lack of knowledge on how aging affects lymphatic vessels certainly contributes to the situation when researchers and clinicians ignore lymph transport-related components of various diseases. Thus, investigation of the mechanisms affecting lymphatic contractile function during aging are extremely important for ongoing attempts to better understand the lymphatic system and to discover the pathogenesis and effective treatment of various aging-associated disorders.Until recently, there were no published reports on systematic studies on aging-associated changes in the active lymph pumps. Due to the profound difficulty of measuring lymph flow in vivo, there are only a few reports demonstrating the measurements of reduced lymph flow in aged animals. [1][2][3] In particular, it was reported 3 that aging significantly decreases lymph flow from the main mesenteric lymph duct by *60% between ages of 3 and 22 mo in rats.During the last years, we obtained important functional and molecular evidence of the aging-associated alterations of contractility in lymphatic vessels, which already widened our knowledge on the biology of aged lymph flow. On the other hand, our recent studies raise new important questions that may link several diseases to impaired coordination between lymphatic function and function of other systems in the aged body. While this review provides some recent answers on current questions in biology of lymphatic aging,...

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confidence: 79%

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confidence: 99%

Aged Lymphatic Contractility: Recent Answers and New Questions

Gashev

Chatterjee

2013

Lymphatic Research and Biology

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“…High concentrations of ROS injure tissues and cause vascular dysfunction (Channon and Guzik, 2002). Accordingly, mice deficient in copper-zinc superoxide dismutase, the cytosol/nuclear SOD, display increased SO, decreased relaxation response to NO, and vascular dysfunction (Didion et al, 2002). Furthermore, administration of superoxide scavengers protects against vascular dysfunction in experimental animal models (Iadecola et al, 1999;Mayhan, 1997).…”

Section: Discussionmentioning

confidence: 99%

Nitric oxide modulates murine yolk sac vasculogenesis and rescues glucose induced vasculopathy

et al. 2004

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Nitric oxide (NO) has been demonstrated to mediate events during ovulation,pregnancy, blastocyst invasion and preimplantation embryogenesis. However,less is known about the role of NO during postimplantation development. Therefore, in this study, we explored the effects of NO during vascular development of the murine yolk sac, which begins shortly after implantation. Establishment of the vitelline circulation is crucial for normal embryonic growth and development. Moreover, functional inactivation of the endodermal layer of the yolk sac by environmental insults or genetic manipulations during this period leads to embryonic defects/lethality, as this structure is vital for transport, metabolism and induction of vascular development. In this study, we describe the temporally/spatially regulated distribution of nitric oxide synthase (NOS) isoforms during the three stages of yolk sac vascular development (blood island formation, primary capillary plexus formation and vessel maturation/remodeling) and found NOS expression patterns were diametrically opposed. To pharmacologically manipulate vascular development,an established in vitro system of whole murine embryo culture was employed. During blood island formation, the endoderm produced NO and inhibition of NO(L-NMMA) at this stage resulted in developmental arrest at the primary plexus stage and vasculopathy. Furthermore, administration of a NO donor did not cause abnormal vascular development; however, exogenous NO correlated with increased eNOS and decreased iNOS protein levels. Additionally, a known environmental insult (high glucose) that produces reactive oxygen species(ROS) and induces vasculopathy also altered eNOS/iNOS distribution and induced NO production during yolk sac vascular development. However, administration of a NO donor rescued the high glucose induced vasculopathy, restored the eNOS/iNOS distribution and decreased ROS production. These data suggest that NO acts as an endoderm-derived factor that modulates normal yolk sac vascular development, and decreased NO bioavailability and NO-mediated sequela may underlie high glucose induced vasculopathy.

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“…Whereas mitochondrial free radicals and mitochondrial manganese SOD (MnSOD) may be important regulators of oxidative stress in the diabetic heart and endothelial cells [11][12][13], Cu/Zn-SOD, the cytosolic isoform, accounts for approximately 50% to 80% of total SOD activity in blood vessels [14,15]. Based on previous findings in humans and animals, we hypothesised that exercise decreases oxidative stress by reducing body weight, improving metabolic parameters and increasing the expression of antioxidant enzymes in the aorta of db/db mice, a routinely used murine model of obesity and type 2 diabetes.…”

Section: Introductionmentioning

confidence: 99%

Exercise restores endothelial function independently of weight loss or hyperglycaemic status in db/db mice

et al. 2008

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Aims/hypothesis Exercise ameliorates oxidative stressmediated diabetic vascular endothelial dysfunction through poorly defined mechanisms. We hypothesised that, in addition to improving metabolic parameters, upregulation of antioxidants such as superoxide dismutase (SOD) mediates exercise-induced reductions of oxidative stress and increased nitric oxide (NO) bioavailability, and also restores vasodilatation. Methods Type 2 diabetic db/db and normoglycaemic wildtype mice were exercised at moderate intensity for 1 h a day for 7 weeks, leading to a 10% body weight loss. Sedentary animals or those undergoing a low-intensity exercise regimen causing non-significant weight loss were also used. We examined aortic endothelial cell function, NO bioavailability and various biomarkers of oxidative stress. Results Moderate-intensity exercise lowered body weight, increased mitochondrial manganese SOD (MnSOD) and both total and phosphorylated (Ser1177) endothelial nitric oxide synthase (eNOS) protein production; it also reduced wholebody (plasma 8-isoprostane) and tissue oxidative stress (nitrotyrosine immunostaining or protein carbonyl levels in the aorta). Low-intensity exercise did not alter body weight; however, it upregulated cytosolic Cu/Zn-SOD instead of MnSOD, and still demonstrated all the above benefits in the db/db aorta. Importantly, both exercise protocols improved endothelial-dependent vasodilatation and NO bioavailability without altering hyperglycaemic status in db/db mice. Conclusions/interpretation Exercise reverses diabetic vascular endothelial dysfunction independently of improvements in body weight or hyperglycaemia. Our data suggest that upregulation of eNOS and specific SOD isoforms could play important roles in improving NO bioavailability, as well as in reversing endothelial dysfunction in type 2 diabetes patients through lifestyle modifications in the management of diabetes.

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Increased Superoxide and Vascular Dysfunction in CuZnSOD-Deficient Mice

Cited by 211 publications

References 63 publications

Aged Lymphatic Contractility: Recent Answers and New Questions

Aged Lymphatic Contractility: Recent Answers and New Questions

Nitric oxide modulates murine yolk sac vasculogenesis and rescues glucose induced vasculopathy

Exercise restores endothelial function independently of weight loss or hyperglycaemic status in db/db mice

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