Inhibition by Hydrogen Sulfide of Rabbit Platelet Aggregation and Calcium Mobilization

Nishikawa, Hiroyuki; Hayashi, Hitomi; Kubo, Satoko; Tsubota-Matsunami, Maho; Sekiguchi, Fumiko; Kawabata, Atsufumi

doi:10.1248/bpb.b13-00018

“…In the advanced atherosclerosis model of Apo E KO mice, subendothelial infiltration of monocytes/macrophages and platelets was observed, suggesting intimate interactions of platelets and macrophages in early atherosclerosis [85]. A recent paper by Nishikawa et al demonstrated the role of hydrogen sulfide (H 2 S), a gasotransmitter, in inhibiting platelet aggregation by interfering the cytosolic Ca 2+ mobilization in a cAMP-dependent manner, comparable to what is observed for nitric oxide (NO) [86]. Studies by us have suggested that functions regulated by NO require the presence and activation of TSPO [87].…”

Section: Results With Discussionmentioning

confidence: 91%

Thrombosis, Atherosclerosis and Atherothrombosis – New Insights and Experimental Protocols

Dimitrova-Shumkovska¹,

Veenman²,

Roim³

et al. 2015

Thrombosis, Atherosclerosis and Atherothrombosis - New Insights and Experimental Protocols

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Previous studies have shown that TSPO as well as apolipoprotein E "po E can be associated with processes such as cholesterol metabolism, oxidative stress, apoptosis, glial activation, inflammation, and immune responses. "s a ligand for cell-surface lipoprotein receptors, apolipoprotein E can prevent atherosclerosis by clearing cholesterol-rich lipoproteins from plasma. Furthermore, TSPO takes part in the regulation of gene expression for proteins involved in adhesion, which potentially may play a role in platelet aggregation. There are indications that the "po E protein is involve in platelet aggregation, while TSPO platelet levels have been found to be increased with various neurological disorders, in particular, in stress-related disorders. The role of platelets in atherogenesis and the potential therapeutic impact of TSPO ligands on disease prevention are of great interest. To determine TSPO binding characteristics in this paradigm, we applied binding assays with [ H]PK on isolated platelets and erythrocyte membranes. The in vivo findings in "po E knockout mice revealed that TSPO levels appear to be enhanced in platelets and erythrocytes of "po E knockout mice, and thus suggest that TSPO and "po E expression may be interconnected in relation to some aspect of the host defense response. Other organs tested, such as liver, testis, brain, heart, aorta, lung, kidney and spleen, did not show a difference in TSPO binding levels between "po E knockout mice and wild-type mice. This suggests that TSPO levels may be part of a feedback control system for steroid production responding to alterations in steroid levels , rather than being regulated by a feed-forward signal provided by cholesterol i.e. TSPO levels in relation to steroidogenesis are not being regulated by cholesterol levels in vivo .

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“…6 C. Analysis of the data does not show any statistical differences between SUL and NOSH-SUL. It should be noted that NOSH-SUL releases NO and H 2 S [29] both of which can have independent anti-platelet properties [41–43] .…”

Section: Resultsmentioning

confidence: 99%

NOSH-sulindac (AVT-18A) is a novel nitric oxide- and hydrogen sulfide-releasing hybrid that is gastrointestinal safe and has potent anti-inflammatory, analgesic, antipyretic, anti-platelet, and anti-cancer properties

Kashfi

¹

,

Chattopadhyay

²

,

Kodela

³

2015

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Sulindac is chemopreventive and has utility in patients with familial adenomatous polyposis; however, side effects preclude its long-term use. NOSH-sulindac (AVT-18A) releases nitric oxide and hydrogen sulfide, was designed to be a safer alternative. Here we compare the gastrointestinal safety, anti-inflammatory, analgesic, anti-pyretic, anti-platelet, and anti-cancer properties of sulindac and NOSH-sulindac administered orally to rats at equimolar doses. Gastrointestinal safety: 6 h post-administration, number/size of hemorrhagic lesions in stomachs were counted. Tissue samples were frozen for PGE2, SOD, and MDA determination. Anti-inflammatory: 1 h after drug administration, the volume of carrageenan-induced rat paw edemas was measured for 5 h. Anti-pyretic: fever was induced by LPS (ip) an hour before administration of the test drugs, core body temperature was measured hourly for 5 h. Analgesic: time-dependent analgesic effects were evaluated by carrageenan-induced hyperalgesia. Antiplatelet: anti-aggregatory effects were studied on collagen-induced platelet aggregation of human platelet-rich plasma. Anti-cancer: We examined the effects of NOSH-sulindac on the growth properties of 12 human cancer cell lines of six different tissue origins. Both agents reduced PGE2 levels in stomach tissue; however, NOSH-sulindac did not cause any stomach ulcers, whereas sulindac caused significant bleeding. Lipid peroxidation induced by sulindac was higher than that from NOSH-sulindac. SOD activity was significantly lowered by sulindac but increased by NOSH-sulindac. Both agents showed similar anti-inflammatory, analgesic, anti-pyretic, and anti-platelet activities. Sulindac increased plasma TNFα whereas this rise was lower in the NOSH-sulindac-treated animals. NOSH-sulindac inhibited the growth of all cancer cell lines studied, with potencies of 1000- to 9000-fold greater than that of sulindac. NOSH-sulindac inhibited cell proliferation, induced apoptosis, and caused G2/M cell cycle block. These results demonstrate that NOSH-sulindac is gastrointestinal safe, and maintains the anti-inflammatory, analgesic, antipyretic, and antiplatelet properties of its parent compound sulinsac, with anti-growth activity against a wide variety of human cancer cells.

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“…More studies may provide deeper insights into how TSPO is involved in molecular biological mechanisms and biological functions of erythrocytes. [86]. Studies by us have suggested that functions regulated by NO require the presence and activation of TSPO [87].…”

Section: Results With Discussionmentioning

confidence: 99%

Thrombosis, Atherosclerosis and Atherothrombosis - New Insights and Experimental Protocols

Mijovski¹

2015

1

0

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Previous studies have shown that TSPO as well as apolipoprotein E "po E can be associated with processes such as cholesterol metabolism, oxidative stress, apoptosis, glial activation, inflammation, and immune responses. "s a ligand for cell-surface lipoprotein receptors, apolipoprotein E can prevent atherosclerosis by clearing cholesterol-rich lipoproteins from plasma. Furthermore, TSPO takes part in the regulation of gene expression for proteins involved in adhesion, which potentially may play a role in platelet aggregation. There are indications that the "po E protein is involve in platelet aggregation, while TSPO platelet levels have been found to be increased with various neurological disorders, in particular, in stress-related disorders. The role of platelets in atherogenesis and the potential therapeutic impact of TSPO ligands on disease prevention are of great interest. To determine TSPO binding characteristics in this paradigm, we applied binding assays with [ H]PK on isolated platelets and erythrocyte membranes. The in vivo findings in "po E knockout mice revealed that TSPO levels appear to be enhanced in platelets and erythrocytes of "po E knockout mice, and thus suggest that TSPO and "po E expression may be interconnected in relation to some aspect of the host defense response. Other organs tested, such as liver, testis, brain, heart, aorta, lung, kidney and spleen, did not show a difference in TSPO binding levels between "po E knockout mice and wild-type mice. This suggests that TSPO levels may be part of a feedback control system for steroid production responding to alterations in steroid levels , rather than being regulated by a feed-forward signal provided by cholesterol i.e. TSPO levels in relation to steroidogenesis are not being regulated by cholesterol levels in vivo .

show abstract

Inhibition by Hydrogen Sulfide of Rabbit Platelet Aggregation and Calcium Mobilization

Cited by 26 publications

References 20 publications

Thrombosis, Atherosclerosis and Atherothrombosis – New Insights and Experimental Protocols

Thrombosis, Atherosclerosis and Atherothrombosis – New Insights and Experimental Protocols

NOSH-sulindac (AVT-18A) is a novel nitric oxide- and hydrogen sulfide-releasing hybrid that is gastrointestinal safe and has potent anti-inflammatory, analgesic, antipyretic, anti-platelet, and anti-cancer properties

Thrombosis, Atherosclerosis and Atherothrombosis - New Insights and Experimental Protocols

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