Oxidative stress activates protein tyrosine kinase and matrix metalloproteinases leading to blood–brain barrier dysfunction

Haorah, James; Ramirez, Servio H.; Schall, Kathy; Smith, Daniel L.; Pandya, Rita; Persidsky, Yuri

doi:10.1111/j.1471-4159.2006.04393.x

Cited by 298 publications

(214 citation statements)

References 64 publications

Supporting

Mentioning

199

Contrasting

Unclassified

Order By: Relevance

“…37 Moreover, it has been demonstrated that oxidative stress can activate MMP-2 and MMP-9 via tyrosine kinase-dependent mechanisms, leading to BBB breakdown. 38 Proinflammatory cytokines are also suggested to induce the release of MMP-9 from brain pericytes in the damaged BBB. 39 Therefore, in T2DM, the accumulation of oxidative stress and inflammation response induce and activate MMPs, which further downregulate TJ proteins and promote swollen astrocytic end-feet, and ultimately lead to BBB dysfunction and subsequent cognitive decline.…”

Section: Discussionmentioning

confidence: 99%

Peroxisome Proliferator-Activated Receptor-γ Activation With Angiotensin II Type 1 Receptor Blockade Is Pivotal for the Prevention of Blood-Brain Barrier Impairment and Cognitive Decline in Type 2 Diabetic Mice

et al. 2012

View full text Add to dashboard Cite

Abstract-We reported previously that an angiotensin II type 1 receptor blocker, telmisartan, improved cognitive decline with peroxisome proliferator-activated receptor-␥ activation; however, the detailed mechanisms are unclear. Enhanced blood-brain barrier (BBB) permeability with alteration of tight junctions is suggested to be related to diabetes mellitus. Therefore, we examined the possibility that telmisartan could attenuate BBB impairment with peroxisome proliferator-activated receptor-␥ activation to improve diabetes mellitus-induced cognitive decline. Type 2 diabetic mice KKA y exhibited impairment of cognitive function, and telmisartan treatment attenuated this. Cotreatment with GW9662, a peroxisome proliferator-activated receptor-␥ antagonist, interfered with these protective effects of telmisartan against cognitive function. BBB permeability was increased in both the cortex and hippocampus in KKA y mice. Administration of telmisartan attenuated this increased BBB permeability. Coadministration of GW9662 reduced this effect of telmisartan. Significant decreases in expression of tight junction proteins and increases in matrix metalloproteinase expression, oxidative stress, and proinflammatory cytokine production were observed in the brain, and treatment with telmisartan restored these changes. Swollen astroglial end-feet in BBB were observed in KKA y mice, and this change in BBB ultrastructure was decreased in telmisartan. These effects of telmisartan were weakened by cotreatment with GW9662. In contrast, administration of another angiotensin II type 1 receptor blocker, losartan, was less effective compared with telmisartan in terms of preventing BBB permeability and astroglial end-foot swelling, and coadministration of GW9662 did not affect the effects of losartan. These findings are consistent with the possibility that, in type 2 diabetic mice, angiotensin II type 1 receptor blockade with peroxisome proliferator-activated receptor-␥ activation by telmisartan may help with protection against cognitive decline by preserving the integrity of the BBB. 1 Impairment of the BBB has been suggested to play a key role in the development and progression of several CNS disorders contributing to cognitive decline.2 Such BBB impairment is mainly caused by hypoxia/ischemia and inflammation. [3][4][5] Type 2 diabetes mellitus (T2DM) has been highlighted as a major risk factor for cognitive decline.6 However, the mechanisms involved are not completely understood. T2DM is characterized by hyperglycemia, hyperinsulinemia, and chronic cerebral microvascular complications. Studies focused on chronic hyperglycemia and increased vascular damage in diabetes mellitus showed that abnormal glucose metabolism results in the generation of reactive oxygen species followed by oxidative stress, mitochondrial dysfunction, and inflammatory response.

show abstract

Section: Discussionmentioning

confidence: 99%

Peroxisome Proliferator-Activated Receptor-γ Activation With Angiotensin II Type 1 Receptor Blockade Is Pivotal for the Prevention of Blood-Brain Barrier Impairment and Cognitive Decline in Type 2 Diabetic Mice

et al. 2012

View full text Add to dashboard Cite

show abstract

“…There are many factors contributing to BBB disruption in ischemia, including generation of oxygen radicals (24,56,58), nitric oxide (22,42), production of vascular endothelial growth factor (67,69), and changes in intracellular calcium (5,26,35). Under normal conditions, the integrity of the BBB is maintained by tight junction complexes between adjacent brain capillary endothelial cells (2).…”

mentioning

confidence: 99%

TRPC-mediated actin-myosin contraction is critical for BBB disruption following hypoxic stress

Hicks

O’Neil

Dubinsky

et al. 2010

American Journal of Physiology-Cell Physiology

View full text Add to dashboard Cite

Hicks K, O'Neil RG, Dubinsky WS, Brown RC. TRPC-mediated actin-myosin contraction is critical for BBB disruption following hypoxic stress. Am J Physiol Cell Physiol 298: C1583-C1593, 2010. First published February 17, 2010 doi:10.1152/ajpcell.00458.2009.-Hypoxia-induced disruption of the blood-brain barrier (BBB) is the result of many different mechanisms, including alterations to the cytoskeleton. In this study, we identified actin-binding proteins involved in cytoskeletal dynamics with quantitative proteomics and assessed changes in subcellular localization of two proteins involved in actin polymerization [vasodilator-stimulated phosphoprotein (VASP)] and cytoskeleton-plasma membrane cross-linking (moesin). We found significant redistribution of both VASP and moesin to the cytoskeletal and membrane fractions of BBB endothelial cells after 1-h hypoxic stress. We also investigated activation of actin-myosin contraction through assessment of phosphorylated myosin light chain (pMLC) with confocal microscopy. Hypoxia caused a rapid and transient increase in pMLC. Blocking MLC phosphorylation through inhibition of myosin light chain kinase (MLCK) with ML-7 prevented hypoxiainduced BBB disruption and relocalization of the tight junction protein ZO-1. Finally, we implicate the transient receptor potential (TRP)C family of channels in mediating these events since blockade of TRPC channels and the associated calcium influx with SKF-96365 prevents hypoxia-induced permeability changes and the phosphorylation of MLC needed for actin-myosin contraction. These data suggest that hypoxic stress triggers alterations to cytoskeletal structure that contribute to BBB disruption and that calcium influx through TRPC channels contributes to these events. cation channels; endothelial cell; stroke; blood-brain barrier; calcium; transient receptor potential C channels BREAKDOWN of the blood-brain barrier (BBB) contributes to edema formation, infarct size, and brain damage following ischemic stroke (3,10,36,39). There are many factors contributing to BBB disruption in ischemia, including generation of oxygen radicals (24, 56, 58), nitric oxide (22, 42), production of vascular endothelial growth factor (67, 69), and changes in intracellular calcium (5,26,35). Under normal conditions, the integrity of the BBB is maintained by tight junction complexes between adjacent brain capillary endothelial cells (2). Changes in BBB permeability are correlated with changes in tight junction structure (33,45,51,59). After hypoxia, this increased permeability is associated with disruptions in the subcellular localization of the tight junction proteins zonula occludens-1 (ZO-1) (43) and occludin (5).A major contributing factor to disruption of the BBB after hypoxia is contraction of the actin-myosin cytoskeleton (23). A recent study demonstrated that inhibition of actin-myosin contraction protected the BBB after hypoxic stress (34); hypoxiainduced BBB disruption was prevented by inhibition of myosin light chain kinase (MLCK), by inhibition of NADPH-oxida...

show abstract

“…In regard to the above, emerging evidence suggests that disruption of the BBB integrity, which can occur not only during SAE, but also during the course of various inflammatory disorders, may be the consequence of endothelial cell damage elicited by circulating bacterial LPS (17,37), proinflammatory cytokines, such as TNF-␣ (1, 39), high levels of ROS (e.g., H 2 0 2 ; Refs. 23,44), and/or NO produced by iNOS (37). In addition, it has been shown that exposure of cultured cerebrovascular endothelial cells to hypoxic insult (31) or serum obtained from multiple sclerosis (MS) patients reduce the expression of tight junctionassociated protein, occludin, and adherence junction protein, VE-cadherin, two major components of the intercellular junctions in the brain microvasculature that help to create and maintain the BBB (40,44).…”

Section: Discussionmentioning

confidence: 99%

Role of endothelial nitric oxide synthase-derived nitric oxide in activation and dysfunction of cerebrovascular endothelial cells during early onsets of sepsis

Handa¹,

Stephen²,

Cepinskas³

2008

American Journal of Physiology-Heart and Circulatory Physiology

View full text Add to dashboard Cite

Handa O, Stephen J, Cepinskas G. Role of endothelial nitric oxide synthase-derived nitric oxide in activation and dysfunction of cerebrovascular endothelial cells during early onsets of sepsis. Am J Physiol Heart Circ Physiol 295: H1712-H1719, 2008. First published August 22, 2008; doi:10.1152/ajpheart.00476.2008.-Sepsis-associated encephalopathy is an early manifestation of sepsis, resulting in a diffuse dysfunction of the brain. Recently, nitric oxide (NO) has been proposed to be one of the key molecules involved in the modulation of inflammatory responses in the brain. The aim of this study was to assess the role of NO in cerebrovascular endothelial cell activation/ dysfunction during the early onsets of sepsis. To this end, we employed an in vitro model of sepsis in which cultured mouse cerebrovascular endothelial cells (MCVEC) were challenged with blood plasma (20% vol/vol) obtained from sham or septic (feces-induced peritonitis, FIP; 6 h) mice. Exposing MCVEC to FIP plasma for 1 h resulted in increased production of reactive oxygen species and NO as assessed by intracellular oxidation of oxidant-sensitive fluorochrome, dihydrorhodamine 123 (DHR 123), and nitrosation of NO-specific probe, DAF-FM, respectively. The latter events were accompanied by dissociation of tight junction protein, occludin, from MCVEC cytoskeletal framework and a subsequent increase in FITC-dextran (3-kDa mol mass) flux across MCVEC grown on the permeable cell culture supports, whereas Evans blue-BSA (65-kDa mol mass) or FITC-dextran (10-kDa mol mass) flux were not affected. FIP plasmainduced oxidant stress, occludin rearrangement, and MCVEC permeability were effectively attenuated by antioxidant, 1-pyrrolidinecarbodithioic acid (PDTC; 0.5 mM), or interfering with nitric oxide synthase (NOS) activity [0.1 mM nitro-L-arginine methyl ester (L-NAME) or endothelial NOS (eNOS)-deficient MCVEC]. However, treatment of MCVEC with PDTC failed to interfere with NO production, suggesting that septic plasma-induced oxidant stress in MCVEC is primarily a NO-dependent event. Taken together, these data indicate that during early sepsis, eNOS-derived NO exhibits proinflammatory characteristics and contributes to the activation and dysfunction of cerebrovascular endothelial cells. oxidant stress; vascular permeability; systemic inflammation; cell culture DISRUPTION OF THE BLOOD-BRAIN barrier (BBB) integrity occurs during a variety of brain-associated pathophysiological conditions such as multiple sclerosis, bacterial/viral meningitis, or brain tumors (16, 39). However, it appears that BBB function can also be impaired as a consequence of systemic inflammation, particularly if the prime cause of systemic inflammation is bacteria (i.e., sepsis) (17, 42).Sepsis-associated encephalopathy (SAE) is an early manifestation of sepsis and is characterized by accelerated reactive oxygen species (ROS) production and increased BBB permeability (17,42,50). It is generally agreed that the main source for ROS production in the organs of nonneural origin, e.g., heart ...

show abstract

Oxidative stress activates protein tyrosine kinase and matrix metalloproteinases leading to blood–brain barrier dysfunction

Cited by 298 publications

References 64 publications

Peroxisome Proliferator-Activated Receptor-γ Activation With Angiotensin II Type 1 Receptor Blockade Is Pivotal for the Prevention of Blood-Brain Barrier Impairment and Cognitive Decline in Type 2 Diabetic Mice

Peroxisome Proliferator-Activated Receptor-γ Activation With Angiotensin II Type 1 Receptor Blockade Is Pivotal for the Prevention of Blood-Brain Barrier Impairment and Cognitive Decline in Type 2 Diabetic Mice

TRPC-mediated actin-myosin contraction is critical for BBB disruption following hypoxic stress

Role of endothelial nitric oxide synthase-derived nitric oxide in activation and dysfunction of cerebrovascular endothelial cells during early onsets of sepsis

Contact Info

Product

Resources

About