NCX 6560, a nitric oxide-releasing derivative of atorvastatin, inhibits cholesterol biosynthesis and shows anti-inflammatory and anti-thrombotic properties

Momi, Stefania; Impagnatiello, Francesco; Guzzetta, Massimiliano; Caracchini, R.; Guglielmini, Giuseppe; Olivieri, Rossana; Monopoli, Angela; Gresele, Paolo

doi:10.1016/j.ejphar.2007.05.014

Cited by 45 publications

(47 citation statements)

References 38 publications

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“…Recent investigations have been working on the development of efficient NO-related materials for clinical demands [5][6][7] . In relation to cardiovascular disease (CVD) therapies, although implants like vascular stents have demonstrated its benefit effects, thrombus formation and intimal hyperplasia are still concerns [6][7][8] .…”

Section: Introductionmentioning

confidence: 99%

Copper-Incorporated Collagen/Catechol Film for in Situ Generation of Nitric Oxide

Luo

Liu

Yao

et al. 2015

ACS Biomater. Sci. Eng.

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Local and continuous release of nitric oxide (NO) has been suggested to be a potential and desirable demand for blood contacting implants. However, the life time of NO release from polymer films is limited by the reservoir of loaded NO donor. In situ generation of NO via catalytic decomposing the endogenous S-nitrosothiols (RSNOs) at the blood/material interface is a novel and challenging approach. Herein, a copper-incorporated film was constructed with the copolymerization of catechols (catechol or epigallocatechin gallate (EGCG)) and collagen. FT-IR results suggested the successful deposition of catechol/collagen copolymer film. The XPS results demonstrated the existence of copper on the surfaces. AFM results demonstrated that copper particles were formed in the thin polymeric film. Copper-incorporated samples presented a capability of generating physiological levels of NO. Difference of the generated amount of NO was associated with the Cu (I) concentration during the testing period, demonstrated by micro-BCA assay. NO-generating films not only significant properties on inhibiting platelet activation and adhesion, but also dramatically decreased smooth muscle cell adhesion. Such copper-incorporated film might suggest potential in the design of vascular devices.

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Section: Introductionmentioning

confidence: 99%

Copper-Incorporated Collagen/Catechol Film for in Situ Generation of Nitric Oxide

Luo

Liu

Yao

et al. 2015

ACS Biomater. Sci. Eng.

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“…In cirrhotic rats though, atorvastatin showed a greater PP lowering effect together with an attenuation of fibrosis and hepatic stellate cell activation1123 and a reduction in neo-angiogenesis in the splanchnic circulation28. NCX 6560, a NO-releasing derivative of atorvastatin, exerts greater lipid-lowering, antithrombotic and anti-inflammatory effects than atorvastatin and prevents statin-induced myopathy29303132.…”

mentioning

confidence: 99%

A Nitric Oxide-Donating Statin Decreases Portal Pressure with a Better Toxicity Profile than Conventional Statins in Cirrhotic Rats

Rodriguez

Raurell

Torres-Arauz

et al. 2017

Sci Rep

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Statins present many beneficial effects in chronic liver disease, but concerns about safety exist. We evaluated the hepatic effects of a nitric oxide-releasing atorvastatin (NCX 6560) compared to conventional statins. Simvastatin, atorvastatin and NCX 6560 were evaluated in four-week bile duct-ligated rats (BDL) simulating decompensated cirrhosis and in thirteen-week carbon tetrachloride (CCl4) intoxicated rats, a model of early cirrhosis. In the BDL model, simvastatin treated rats showed high mortality and the remaining animals presented muscular and hepatic toxicity. At equivalent doses, NCX 6560 eliminated hepatic toxicity and reduced muscular toxicity (60–74%) caused by atorvastatin in the more advanced BDL model; toxicity was minimal in the CCl4 model. Atorvastatin and NCX 6560 similarly reduced portal pressure without changing systemic hemodynamics in both models. Atorvastatin and NCX 6560 caused a mild decrease in liver fibrosis and inflammation and a significant increase in intrahepatic cyclic guanosine monophosphate. NCX 6560 induced a higher intrahepatic vasoprotective profile (activated endothelial nitric oxide synthase and decreased platelet/endothelial cell adhesion molecule-1), especially in the CCl4 model, suggesting a higher benefit in early cirrhosis. In conclusion, NCX 6560 improves the liver profile and portal hypertension of cirrhotic rats similarly to conventional statins, but with a much better safety profile.

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“…26,27 Briefly, mice were challenged with 0.1 mL of a mixture containing 200 g/mL of collagen and 1.2 g/mL of epinephrine rapidly injected into one of the tail veins. The mortality of mice in each group was monitored over 15 minutes and data are presented as percentage of animals dead over the total number of animals tested.…”

Section: Platelet Pulmonary Thromboembolismmentioning

confidence: 99%

“…on May 9, 2018. by guest www.bloodjournal.org From number of identifiable lung vessels per field was counted and the percentage of them occluded by platelet thrombi was annotated. 26,27 Femoral artery thrombosis Photochemical-induced femoral artery thrombosis was induced in anesthetized mice by a method described previously. 23,27,28 Briefly, mice were anaesthetized by xylazine (5 mg/kg IP) and ketamine (60 mg/kg IP) and placed on a heated operating table.…”

Section: Lung Histologymentioning

confidence: 99%

Impaired thrombin-induced platelet activation and thrombus formation in mice lacking the Ca2+-dependent tyrosine kinase Pyk2

Canobbio¹,

Cipolla

Consonni³

et al. 2013

Blood

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Key Points• The tyrosine kinase Pyk2 regulates a p38MAPK-cPLA2 pathway required for thrombin-induced thromboxane A2 production and platelet aggregation.• Pyk2 deletion in mice confers protection against pulmonary thromboembolism and arterial thrombosis.In the present study, we used a knockout murine model to analyze the contribution of the Ca 2؉ -dependent focal adhesion kinase Pyk2 in platelet activation and thrombus formation in vivo. We found that Pyk2-knockout mice had a tail bleeding time that was slightly increased compared with their wild-type littermates. Moreover, in an in vivo model of femoral artery thrombosis, the time to arterial occlusion was significantly prolonged in mice lacking Pyk2. Pyk2-deficient mice were also significantly protected from collagen plus epinephrine-induced pulmonary thromboembolism. Ex vivo aggregation of Pyk2-deficient platelets was normal on stimulation of glycoprotein VI, but was significantly reduced in response to PAR4-activating peptide, low doses of thrombin, or U46619. Defective platelet aggregation was accompanied by impaired inside-out activation of integrin ␣ IIb ␤ 3 and fibrinogen binding. Granule secretion was only slightly reduced in the absence of Pyk2, whereas a marked inhibition of thrombin-induced thromboxane A 2 production was observed, which was found to be responsible for the defective aggregation. Moreover, we have demonstrated that Pyk2 is implicated in the signaling pathway for cPLA 2 IntroductionPyk2, also known as RAFTK or CAD␤, is a nonreceptor tyrosine kinase that is highly homologous to the focal adhesion kinase FAK and is predominantly expressed in the CNS and hematopoietic cells. 1-3 Like FAK, Pyk2 does not possess SH2 or SH3 domains, but has a centrally located catalytic domain flanked by an N-terminal FERM domain and a C-terminal focal adhesion targeting FAT domain. Pyk2 can be tyrosine phosphorylated and activated by a variety of different cellular stimuli, including cytokines, growth factors, agonists of G-protein-coupled receptors (GPCRs), integrin ligands, and stress stimuli. [3][4][5][6] Typically, Pyk2 activation is mediated by both Src kinase-and cytosolic Ca 2ϩ -dependent pathways. Src kinases phosphorylate Pyk2 at Tyr579, Tyr580, and Tyr881, increasing the catalytic activity of the kinase and promoting autophosphorylation on Tyr402 in the FERM domain. 5,6 Even in the absence of Src-mediated phosphorylation, Pyk2 can be activated on increase of the cytosolic Ca 2ϩ concentration. [4][5][6][7] It has been shown that Ca 2ϩ and calmodulin bind to the N-terminal FERM domain of Pyk2, triggering Pyk2 dimerization, activation, and autophosphorylation at Tyr402. 8 Phosphorylated Tyr402 is a binding site for the SH2 domain of Src. 5,6 Therefore, Pyk2 is a kinase that can link Ca 2ϩ -based signaling pathways to protein tyrosine phosphorylation.Some observations reported over the past 2 decades have implicated Pyk2 in platelet activation. Pyk2 is highly expressed in megakaryocytes and platelets and is rapidly phosphorylated on stimulation with se...

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NCX 6560, a nitric oxide-releasing derivative of atorvastatin, inhibits cholesterol biosynthesis and shows anti-inflammatory and anti-thrombotic properties

Cited by 45 publications

References 38 publications

Copper-Incorporated Collagen/Catechol Film for in Situ Generation of Nitric Oxide

Copper-Incorporated Collagen/Catechol Film for in Situ Generation of Nitric Oxide

A Nitric Oxide-Donating Statin Decreases Portal Pressure with a Better Toxicity Profile than Conventional Statins in Cirrhotic Rats

Impaired thrombin-induced platelet activation and thrombus formation in mice lacking the Ca2+-dependent tyrosine kinase Pyk2

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