A Nitric Oxide-Donating Statin Decreases Portal Pressure with a Better Toxicity Profile than Conventional Statins in Cirrhotic Rats.
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SUBMITTER: Rodriguez S
PROVIDER: S-EPMC5233977 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Background and purposeStatins, a major component of the prevention of cardiovascular disease, aid progenitor cell functions in vivo and in vitro. Statins bearing a NO-releasing moiety were developed for their enhanced anti-inflammatory/anti-thrombotic properties. Here, we investigated if the NO-donating atorvastatin (NCX 547) improved the functions of circulating angiogenic cells (CACs).Experimental approachCirculating angiogenic cells (CACs) were prepared from peripheral blood monocytes of healthy volunteers and type-2 diabetic patients and were cultured in low (LG) or high glucose (HG) conditions, in presence of atorvastatin or NCX 547 (both at 0.1 µM) or vehicle. Functional assays (outgrowth, proliferation, viability, senescence and apoptosis) were performed in presence of the endothelial NOS inhibitor L-NIO, the NO scavenger c-PTIO or vehicle.Key resultsCulturing in HG conditions lowered NO in CACs, inhibited outgrowth, proliferation, viability and migration, and induced cell senescence and apoptosis. NCX 547 fully restored NO levels and functions of HG-cultured CACs, while atorvastatin prevented only apoptosis in CACs. The activity of Akt, a pro-survival kinase, was increased by atorvastatin in LG-cultured but not in HG-cultured CACs, whereas NCX 547 increased Akt activity in both conditions. L-NIO partially blunted and c-PTIO prevented NCX 547-induced improvements in CAC functions. Finally, NCX 547 improved outgrowth and migration of CACs prepared from patients with type 2 diabetes.Conclusions and implicationsNCX 547 was more effective than atorvastatin in preserving functions of CACs. This property adds to the spectrum of favourable actions that would make NO-releasing statins more effective agents for treating cardiovascular disease.
| S-EPMC3188894 | biostudies-literature
Project description:Liver cirrhosis but also portal vein obstruction cause portal hypertension (PHT) and angiogenesis. This study investigated the differences of angiogenesis in cirrhotic and non-cirrhotic PHT with special emphasis on the canonical (Shh/Gli) and non-canonical (Shh/RhoA) hedgehog pathway. Cirrhotic (bile duct ligation/BDL; CCl4 intoxication) and non-cirrhotic (partial portal vein ligation/PPVL) rats received either atorvastatin (15 mg/kg; 7d) or control chow before sacrifice. Invasive hemodynamic measurement and Matrigel implantation assessed angiogenesis in vivo. Angiogenesis in vitro was analysed using migration and tube formation assay. In liver and vessel samples from animals and humans, transcript expression was analyzed using RT-PCR and protein expression using Western blot. Atorvastatin decreased portal pressure, shunt flow and angiogenesis in cirrhosis, whereas atorvastatin increased these parameters in PPVL rats. Non-canonical Hh was upregulated in experimental and human liver cirrhosis and was blunted by atorvastatin. Moreover, atorvastatin blocked the non-canonical Hh-pathway RhoA dependently in activated hepatic steallate cells (HSCs). Interestingly, hepatic and extrahepatic Hh-pathway was enhanced in PPVL rats, which resulted in increased angiogenesis. In summary, statins caused contrary effects in cirrhotic and non-cirrhotic portal hypertension. Atorvastatin inhibited the non-canonical Hh-pathway and angiogenesis in cirrhosis. In portal vein obstruction, statins enhanced the canonical Hh-pathway and aggravated PHT and angiogenesis.
| S-EPMC4585958 | biostudies-literature
Project description:BackgroundStatins may improve outcomes in patients with cirrhosis. We performed a systematic review and meta-analysis to evaluate the effect of statins on patients with cirrhosis and related complications, especially portal hypertension and variceal haemorrhage.MethodsStudies were searched in the PubMed, Embase and Cochrane library databases up to February 2019. The outcomes of interest were associations between statin use and improvement in portal hypertension (reduction >20% of baseline or <12 mm Hg) and the risk of variceal haemorrhage. The relative risk (RR) with a 95% CI was pooled and calculated using a random effects model. Subgroup analyses were performed based on the characteristics of the studies.ResultsEight studies (seven randomised controlled trials (RCTs) and one observational study) with 3195 patients were included. The pooled RR for reduction in portal hypertension was 1.91 (95% CI, 1.04 to 3.52; I2=63%) in six RCTs. On subgroup analysis of studies that used statin for 1 month, the RR was 2.01 (95% CI, 1.31 to 3.10; I2=0%); the pooled RR for studies that used statins for 3 months was 3.76 (95% CI, 0.36 to 39.77; I2=75%); the pooled RR for studies that used non-selective beta-blockers in the control group was 1.42 (95% CI, 0.82 to 2.45; I2=64%); the pooled RR for studies that used a drug that was not reported in the control group was 4.21 (95% CI, 1.52 to 11.70; I2=0%); the pooled RR for studies that used simvastatin was 2.20 (95% CI, 0.92 to 5.29; I2=69%); RR for study using atorvastatin was 1.82 (95% CI, 1.00 to 3.30). For the risk of a variceal haemorrhage, the RR based on an observational study was 0.47 (95% CI, 0.23 to 0.94); in two RCTs, the pooled RR was 0.88 (95% CI, 0.52 to 1.50; I2=0%). Overall, the summed RR was 0.64 (95% CI, 0.42 to 0.99; I2=6%).ConclusionStatins may improve hypertension and decrease the risk of variceal haemorrhage according to our assessment. However, further and larger RCTs are needed to confirm this conclusion.
| S-EPMC6661584 | biostudies-literature
Project description:Background & aimsWe aimed to evaluate long-term outcome of patients with chronic non-cirrhotic extrahepatic portal vein obstruction (CNC-EHPVO) who underwent portal vein recanalisation (PVR) without transjugular intrahepatic portosystemic shunt (TIPS) insertion and to determine factors predicting PVR failure and stent occlusion.MethodsThis retrospective monocentric study included all patients who underwent PVR without TIPS insertion in the context of CNC-EHPVO between the years 2000 and 2019. Primary patency was defined by the absence of a complete stent occlusion on follow-up imaging.ResultsA total of 31 patients underwent PVR with a median follow-up of 52 months (24-82 months). Indications were gastrointestinal bleeding (n = 13), abdominal pain attributed to CNC-EHPVO (n = 7), prior to abdominal surgery (n = 4), and others (n = 7). Technical success was obtained in 27 patients. PVR failure was associated with extension within the intrahepatic portal veins (p = 0.005) and recanalisation for abdominal pain (p = 0.02). Adverse events occurred in 6 patients with no mortality. Anticoagulation was administered in 21 patients after technical success of PVR. In patients with technical success, 5-year primary patency was 73% and was associated with improved muscle mass (p = 0.007) and decreased spleen volume (p = 0.01) at 1 year. Furthermore, 21 (78%) patients with PVR technical success were free of portal hypertension complication at 5 years.ConclusionsPVR without TIPS insertion was feasible and safe in selected patients with CNC-EHPVO and portal hypertension with past or expected complications. Primary patency at 5 years was obtained in 3 of 4 patients with technical success of PVR and was associated with a control of complications of CNC-EHPVO. PVR was associated with improvement of sarcopenia and decreased spleen volume at 1 year.Lay summaryPatients with chronic obstruction of the portal vein and without cirrhosis or malignancy can develop complications related to the high pressure in the venous system. The present study reports long-term favourable outcome of patients in whom the obstruction was treated with stents.
| S-EPMC9253474 | biostudies-literature
Project description:BackgroundNitric oxide-releasing drugs are used for cardiovascular diseases; however, their effects on the tumor immune microenvironment are less clear. Therefore, this study explored the impact of nitric oxide donors on tumor progression in immune-competent mice.MethodsThe effects of three different nitric oxide-releasing compounds (SNAP, SNP, and ISMN) on tumor growth were studied in tumor-bearing mouse models. Three mouse tumor models were used: B16F1 melanoma and LL2 lung carcinoma in C57BL/6 mice, CT26 colon cancer in BALB/c mice, and LL2 lung carcinoma in NOD/SCID mice. After nitric oxide treatment, splenic cytokines and lymphocytes were analyzed by cytokine array and flow cytometry, and tumor-infiltrating lymphocytes in the TME were analyzed using flow cytometry and single-cell RNA sequencing.ResultsLow doses of three exogenous nitric oxide donors inhibited tumor growth in two immunocompetent mouse models but not in NOD/SCID immunodeficient mice. Low-dose nitric oxide donors increase the levels of splenic cytokines IFN-γ and TNF-α but decrease the levels of cytokines IL-6 and IL-10, suggesting an alteration in Th2 cells. Nitric oxide donors increased the number of CD8+ T cells with activation gene signatures, as indicated by single-cell RNA sequencing. Flow cytometry analysis confirmed an increase in infiltrating CD8+ T cells and dendritic cells. The antitumor effect of nitric oxide donors was abolished by depletion of CD8+ T cells, indicating the requirement for CD8+ T cells. Tumor inhibition correlated with a decrease in a subtype of protumor macrophages and an increase in a subset of Arg1-positive macrophages expressing antitumor gene signatures. The increase in this subset of macrophages was confirmed by flow cytometry analysis. Finally, the combination of low-dose nitric oxide donor and cisplatin induced an additive cancer therapeutic effect in two immunocompetent animal models. The enhanced therapeutic effect was accompanied by an increase in the cells expressing the gene signature of NK cell.ConclusionsLow concentrations of exogenous nitric oxide donors inhibit tumor growth in vivo by regulating T cells and macrophages. CD8+ T cells are essential for antitumor effects. In addition, low-dose nitric oxide donors may be combined with chemotherapeutic drugs in cancer therapy in the future.
| S-EPMC9840268 | biostudies-literature
Project description:Background and aimPortal hypertension has been reported in association with acquired and primary immune deficiencies without a comprehensive description of associated spleno-portal axis abnormalities. Pathological mechanisms are poorly defined.MethodsObservational, single centre study with the aim of assessing the prevalence of spleno-portal axis abnormalities in an unselected cohort of 123 patients with primary antibody deficiencies and without known causes of liver diseases regularly followed up for a mean time of 18 ± 14 years. A cumulative period of 1867 patients-year was analysed. Clinical and immunological data, abdominal ultrasounds, CT scans, and endoscopy features were included in the analysis.ResultsTwenty-five percent of patients with primary antibody deficiencies had signs of portal vein enlargement but only 4% of them had portal hypertension, with portal systemic collaterals. Liver biopsies showed liver sinusoids congestive dilatation, endothelization, and micronodularity fulfilling the criteria for noncirrhotic portal hypertension. Patients with portal vein enlargement had severe clinical and immunological phenotypes.ConclusionsIn primary antibody deficient patients, infections, inflammations, splenomegaly, increased blood venous flow, and lymphocyte abnormalities contribute to establishment of liver damage possibly leading to noncirrhotic portal hypertension. Patients with primary antibody deficiency should be considered a good model to give insight into the pathological mechanisms underlying noncirrhotic portal hypertension.
| S-EPMC3988706 | biostudies-literature
Project description:BACKGROUND:Histologic features of idiopathic non-cirrhotic portal hypertension (INCPH) may overlap with those without INCPH. Recently, these features have been recognized as part of the larger spectrum of porto-sinusoidal vascular disease (PSVD). We assessed interobserver agreement on histologic features that are commonly associated with INCPH and studied whether a provision of relevant clinical history improves interobserver agreement. METHODS:The examined histologic features include lobular (such as anisocytosis, nodular regeneration, sinusoidal dilatation, increased parenchymal draining veins, and incomplete fibrous septa) and portal tract changes (such as paraportal shunting vessel(s), portal tract remnant, increased number of portal vessels, and obliterative portal venopathy). Thirty-four archived liver samples from patients with (group A) and without (group B) INCPH were retrieved. A total of 90 representative images of lobules (L) and portal tracts (P) were distributed among 9 liver pathologists blinded to true clinical history. Each pathologist answered multiple choice questions based on the absence (Q1) or presence (Q2) of clinical history of portal hypertension. Fleiss' kappa coefficient analysis (unweighted) was performed to assess interobserver agreement on normal versus abnormal diagnosis, in L and P, based on Q1 and Q2. RESULTS:The kappa values regarding normal versus abnormal diagnosis were 0.24, 0.24, 0.18 and 0.18 for L-Q1, L-Q2, P-Q1, and P-Q2, respectively. With true clinical history provided, the kappa values were L- 0.32, P-0.17 for group A and L-0.12, P-0.14 for group B. Four pathologists changed their assessments based on the provided history. Interobserver agreement on the interpretation of L and P as normal versus abnormal was slight to fair regardless of provision of clinical history. CONCLUSIONS:Our findings indicate that the histologic features of INCPH/PSVD are not limited to patients with portal hypertension and are subject to significant interobserver variation.
| S-EPMC7583235 | biostudies-literature
Project description:Background and aims: There are considerable evidences demonstrating that angiogenesis and chronic inflammation are mutually dependent. However, although cirrhosis progression is characterized with a chronic hepatic inflammatory process, this connection is not sufficiently explored as a therapeutic strategy. Therefore, this study was aimed to assess the potential benefits of targeting angiogenesis in cirrhotic livers to modulate inflammation and fibrosis. For this purpose, we evaluate the therapeutic utility of angiogenesis inhibitors. Methods: The in vivo effects of angiogenesis inhibitors were monitored in liver of cirrhotic rats by measuring angiogenesis, inflammatory infiltrate, fibrosis, a-smooth muscle actin (a-SMA) accumulation, differential gene expression (by microarrays), and portal pressure. Results: Cirrhosis progression was associated with a significant enhancement of vascular density and expression of vascular endothelial growth factor-A (VEGF-A), angiopoietin-1, angiopoietin-2 and placental growth factor (PlGF) in cirrhotic livers. The newly formed hepatic vasculature expressed vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1). Interestingly, the expression of these adhesion molecules correlated well with local inflammatory infiltrate. Livers of cirrhotic rats treated with angiogenesis inhibitors presented a significant decrease in hepatic vascular density, inflammatory infiltrate, a-SMA abundance, collagen expression and portal pressure. Conclusion: Angiogenesis inhibitors may offer a potential novel therapy for cirrhosis due to its multiple mechanisms of action against angiogenesis, inflammation and fibrosis in cirrhotic livers. Keywords: angiogenesis, cirrhosis, liver, Affymetrix, fibrosis
2007-10-18 | GSE6929 | GEO
Project description:BackgroundCirculating cirrhotic endothelial progenitor cells (EPC) interact with both liver sinusoidal endothelial cells (LSEC) and hepatic stellate cells (HSC) and promote angiogenesis in vitro. This study evaluated the effect of cirrhotic and control EPCs on hepatic angiogenesis, microcirculation, and fibrosis in vivo in rat models of cirrhosis.MethodologyAnimal models of cirrhosis were prepared by bile duct ligation (BDL). Circulating EPCs isolated from healthy human and cirrhotic blood were characterized by flow cytometry, cultured and administered through the tail vein in BDL rats after 2 weeks of ligation. The cells were given thrice a week for 2 weeks. The untreated group of BDL rats received only saline. Fibrosis was evaluated by Masson's trichrome staining. Dedifferentiated LSECs were identified by the expression of CD31, and activated HSCs were marked as alpha-SMA-positive cells and were studied by immunohistochemistry and western blotting in saline-, healthy EPC-, and cirrhotic EPC-treated rats. In vivo, hepatic and systemic hemodynamic parameters were evaluated. Liver functions were evaluated.ResultsIn comparison to controls, BDL rats revealed an increase of fibrosis and angiogenesis. Among the treated rats, cirrhotic EPC-treated rats had increased fibrosis grade as compared to healthy EPC-treated and saline-treated rats. There was an increase of both fibrosis and angiogenesis markers, alpha-SMA and CD31 in cirrhotic EPC-treated rats as compared to healthy EPC-treated and saline-treated rats in immunohistochemistry and western blot studies. Cirrhotic EPC-treated BDL rats had high portal pressure and portal blood flow with significantly elevated hepatic vascular resistance in comparison with healthy EPC- and saline-treated BDL animals, without significant differences in mean arterial pressure. Cirrhotic EPC-treated BDL rats also showed a substantial increase in the hepatic expression of angiogenic receptors, VEGFR2 and CXCR4 in comparison with saline-treated rats.ConclusionThe study suggests that transplantation of cirrhotic EPCs enhances LSEC differentiation and angiogenesis, activates HSCs and worsens fibrosis, thus resulting in hepatic hemodynamic derangements in BDL-induced cirrhosis.
| S-EPMC7300214 | biostudies-literature
Project description:Liver cirrhosis is a frequent condition with high impact on patients' life expectancy and health care systems. Cirrhotic portal hypertension (PH) gradually develops with deteriorating liver function and can lead to life-threatening complications. Other than an increase in intrahepatic flow resistance due to morphological remodeling of the organ, a functional dysregulation of the sinusoids, the smallest functional units of liver vasculature, plays a pivotal role. Vascular tone is primarily regulated by the nitric oxide-cyclic guanosine monophosphate (NO-cGMP) pathway, wherein soluble guanylate cyclase (sGC) and phosphodiesterase-5 (PDE-5) are key enzymes. Recent data showed characteristic alterations in the expression of these regulatory enzymes or metabolite levels in liver cirrhosis. Additionally, a disturbed zonation of the components of this pathway along the sinusoids was detected. This review describes current knowledge of the pathophysiology of PH with focus on the enzymes regulating cGMP availability, i.e., sGC and PDE-5. The results have primarily been obtained in animal models of liver cirrhosis. However, clinical and histochemical data suggest that the new biochemical model we propose can be applied to human liver cirrhosis. The role of PDE-5 as potential target for medical therapy of PH is discussed.
| S-EPMC7503357 | biostudies-literature