Protein disulphide isomerase in platelet function

Manickam, Nagaraj; Sun, Xiuhua; Li, Mengru; Gazitt, Yair; Essex, David W.

doi:10.1111/j.1365-2141.2007.06898.x

Cited by 53 publications

(56 citation statements)

References 42 publications

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“…Cys residues are conserved in structural proteins such as actin and docking proteins such as 14-3-3. Oxidation of Cys residues in ␣IIb␤3 integrin controls platelet activation (43,99,118). Cys-rich regions are present in plasma membrane receptors and ion channels, including the NMDA receptors, EGF receptor, and others.…”

Section: The Redox Hypothesismentioning

confidence: 99%

Radical-free biology of oxidative stress

Jones¹

2008

American Journal of Physiology-Cell Physiology

996

834

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Free radical-induced macromolecular damage has been studied extensively as a mechanism of oxidative stress, but large-scale intervention trials with free radical scavenging antioxidant supplements show little benefit in humans. The present review summarizes data supporting a complementary hypothesis for oxidative stress in disease that can occur without free radicals. This hypothesis, which is termed the "redox hypothesis," is that oxidative stress occurs as a consequence of disruption of thiol redox circuits, which normally function in cell signaling and physiological regulation. The redox states of thiol systems are sensitive to twoelectron oxidants and controlled by the thioredoxins (Trx), glutathione (GSH), and cysteine (Cys). Trx and GSH systems are maintained under stable, but nonequilibrium conditions, due to a continuous oxidation of cell thiols at a rate of about 0.5% of the total thiol pool per minute. Redox-sensitive thiols are critical for signal transduction (e.g., H-Ras, PTP-1B), transcription factor binding to DNA (e.g., Nrf-2, nuclear factor-B), receptor activation (e.g., ␣IIb␤3 integrin in platelet activation), and other processes. Nonradical oxidants, including peroxides, aldehydes, quinones, and epoxides, are generated enzymatically from both endogenous and exogenous precursors and do not require free radicals as intermediates to oxidize or modify these thiols. Because of the nonequilibrium conditions in the thiol pathways, aberrant generation of nonradical oxidants at rates comparable to normal oxidation may be sufficient to disrupt function. Considerable opportunity exists to elucidate specific thiol control pathways and develop interventional strategies to restore normal redox control and protect against oxidative stress in aging and age-related disease.thioredoxin; glutathione; cysteine; hydrogen peroxide; redox signaling; protein thiol ONE OF THE GREAT REDOX BIOLOGISTS of the past century, Howard S. Mason, professed that to advance science, a scientist must interpret observations at the limit of their meaning. The present review of the redox biology of thiol systems addresses the possibility that disruption of the function and homeostasis of thiol systems is the most central feature of oxidative stress that contributes to mechanisms of aging and age-related disease. I have termed this the "redox hypothesis" to facilitate distinction from free radical hypotheses.Many proteins contain redox-sensitive thiols, and reactions of thiol systems occur largely by nonradical two-electron transfers. Accumulating data show that central thiol-disulfide couples are maintained under nonequilibrium conditions in biological systems. This presents a condition wherein changes in abundance and distribution of redox catalysts and changes in rates of generation of relevant oxidants (e.g., peroxides) and precursors for NADPH supply can account for pathological effects of oxidative stress through altered functions of enzymes, receptors, transporters, transcription factors, and structural elements, without free ra...

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Section: The Redox Hypothesismentioning

confidence: 99%

Radical-free biology of oxidative stress

Jones¹

2008

American Journal of Physiology-Cell Physiology

996

834

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“…Antibody-mediated inhibition of PDI blocks platelet aggregation in vitro (2,4,5). Quercetin-3-rutinoside has previously been demonstrated to inhibit platelet aggregation induced by collagen or ADP (19,20).…”

Section: Quercetin-3-rutinoside Analogs As Pdi Inhibitorsmentioning

confidence: 99%

“…Although the substrates activated by PDI during thrombus formation remain unknown, candidates have been proposed. PDI has been implicated in α IIb β 3 -mediated platelet aggregation (2,24). Antibodies directed at PDI inhibit platelet aggregation in vitro (4), and this effect has been attributed in part to the influence of PDI on α IIb β 3 conformation (4, 25).…”

Section: Figurementioning

confidence: 99%

“…Despite having a C-terminal endoplasmic reticulum retention sequence, PDI has been identified at many diverse subcellular locations outside the endoplasmic reticulum. It has biological functions on the cell surfaces of lymphocytes, hepatocytes, platelets, and endothelial cells (2)(3)(4)(5)(6). Platelets are a rich source of extracellular PDI, expressing this protein on their surface and also secreting PDI in response to thrombin stimulation (5,7).…”

Section: Introductionmentioning

confidence: 99%

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Protein disulfide isomerase inhibitors constitute a new class of antithrombotic agents

Jasuja

Passam²,

Kennedy³

et al. 2012

J. Clin. Invest.

261

342

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Thrombosis, or blood clot formation, and its sequelae remain a leading cause of morbidity and mortality, and recurrent thrombosis is common despite current optimal therapy. Protein disulfide isomerase (PDI) is an oxidoreductase that has recently been shown to participate in thrombus formation. While currently available antithrombotic agents inhibit either platelet aggregation or fibrin generation, inhibition of secreted PDI blocks the earliest stages of thrombus formation, suppressing both pathways. Here, we explored extracellular PDI as an alternative target of antithrombotic therapy. A high-throughput screen identified quercetin-3-rutinoside as an inhibitor of PDI reductase activity in vitro. Inhibition of PDI was selective, as quercetin-3-rutinoside failed to inhibit the reductase activity of several other thiol isomerases found in the vasculature. Cellular assays showed that quercetin-3-rutinoside inhibited aggregation of human and mouse platelets and endothelial cell-mediated fibrin generation in human endothelial cells. Using intravital microscopy in mice, we demonstrated that quercetin-3-rutinoside blocks thrombus formation in vivo by inhibiting PDI. Infusion of recombinant PDI reversed the antithrombotic effect of quercetin-3-rutinoside. Thus, PDI is a viable target for small molecule inhibition of thrombus formation, and its inhibition may prove to be a useful adjunct in refractory thrombotic diseases that are not controlled with conventional antithrombotic agents.

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“…Although having a C-terminal endoplasmic reticulum retention sequence, PDI has been identified at many diverse subcellular locations outside the endoplasmic reticulum. It has biological functions on the cell surfaces of lymphocytes, hepatocytes, platelets, and endothelial cells (Manickam et al, 2008;Hotchkiss et al, 1998;Essex, Li, 1999;Burgess et al, 2000;Bennett et al, 2000).…”

Section: Protein Disulfide Isomerase (Pdi)mentioning

confidence: 99%

Rutin- potent natural thrombolytic agent

Dar

Tabassum

2012

Int Curr Pharm J

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Thrombosis, the formation of blood clots, is a cause not only of heart attacks and strokes, but of deep venous thrombosis (DVT) and pulmonary embolism as well. The number one killer of Americans is a blood clot that blocks blood flow to the heart or to the brain and approximately half of all morbidity and mortality in the United States can be attributed to heart attack or stroke. All the blood clot related conditions are life-threatening, and so there is a need for safe, effective and preventive treatment. A natural substance rutin, also called rutoside, is a citrus flavonoid glycoside found in Fagopyrum esculentum (buckwheat), the leaves and petioles of Rheum species, and Asparagus. This flavonoid compound has shown effective thrombolytic activity (prevents the formation of blood clots) by blocking the enzyme protein disulfide isomerase (PDI) found in all cells involved in blood clotting. Food and Drug Administration (FDA) has established that rutin is safe and, thus provides a safe and inexpensive drug that could reduce recurrent clots and help save thousands of lives.DOI: http://dx.doi.org/10.3329/icpj.v1i12.12454 International Current Pharmaceutical Journal 2012, 1(12): 431-435

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Protein disulphide isomerase in platelet function

Cited by 53 publications

References 42 publications

Radical-free biology of oxidative stress

Radical-free biology of oxidative stress

Protein disulfide isomerase inhibitors constitute a new class of antithrombotic agents

Rutin- potent natural thrombolytic agent

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