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      Investigation of the Effects of Some Cardiovascular Drugs on Angiogenesis by Transgenic Zebrafish

      1 , 2 , 3 ,
      Mediators of Inflammation

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          Angiogenesis contributes to the pathophysiology of cardiovascular disease (CVD). Some cardiovascular drugs used in the treatment of CVD have an effect on the process of angiogenesis.


          Transgenic Tg (flk1: EGFP) zebrafish embryos were used to identify the effects of some cardiovascular drugs on angiogenesis during vertebral development in vivo. Zebrafish embryos at a one-cell stage or two-cell stage were cultured with embryo medium containing cardiovascular drugs at a final solvent concentration of 0.5% (V/V) dimethyl sulfoxide (DMSO) for 24 hours in 24-well plates.


          We found that 6 drugs including isosorbide mononitrate, amlodipine, bisoprolol fumarate, carvedilol, irbesartan, and rosuvastatin calcium may affect angiogenesis by vascular endothelial growth factor (VEGF) signaling pathway.


          These new findings of some cardiovascular drugs should improve the treatment of cardiovascular diseases.

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          Most cited references31

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          Statins have biphasic effects on angiogenesis.

          Statins inhibit HMG-CoA reductase to reduce the synthesis of cholesterol and isoprenoids that modulate diverse cell functions. We investigated the effect of the statins cerivastatin and atorvastatin on angiogenesis in vitro and in vivo. Endothelial cell proliferation, migration, and differentiation were enhanced at low concentrations (0.005 to 0.01 micromol/L) but significantly inhibited at high statin concentrations (0.05 to 1 micromol/L). Antiangiogenic effects at high concentrations were associated with decreased endothelial release of vascular endothelial growth factor and increased endothelial apoptosis and were reversed by geranylgeranyl pyrophosphate. In murine models, inflammation-induced angiogenesis was enhanced with low-dose statin therapy (0.5 mg x kg(-1) x d(-1)) but significantly inhibited with high concentrations of cerivastatin or atorvastatin (2.5 mg x kg(-1) x d(-1)). Despite the fact that high-dose statin treatment was effective at reducing lipid levels in hyperlipidemic apolipoprotein E-deficient mice, it impaired rather than enhanced angiogenesis. Finally, high-dose cerivastatin decreased tumor growth and tumor vascularization in a murine Lewis lung cancer model. HMG-CoA reductase inhibition has a biphasic dose-dependent effect on angiogenesis that is lipid independent and associated with alterations in endothelial apoptosis and vascular endothelial growth factor signaling. Statins have proangiogenic effects at low therapeutic concentrations but angiostatic effects at high concentrations that are reversed by geranylgeranyl pyrophosphate. At clinically relevant doses, statins may modulate angiogenesis in humans via effects on geranylated proteins.
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            Drugs that induce repolarization abnormalities cause bradycardia in zebrafish.

            Drug-induced QT prolongation and torsades de pointes remain significant and often unpredictable clinical problems. Current in vitro preclinical assays are limited by biological simplicity, and in vivo models suffer from expense and low throughput. During a screen for the effects of 100 small molecules on the heart rate of the zebrafish, Danio rerio, we found that drugs that cause QT prolongation in humans consistently caused bradycardia and AV block in the zebrafish. Of 23 such drugs tested, 18 were positive in this initial screen. Poor absorption explained 4 of 5 false-negative results, as demonstrated by microinjection. Overall, 22 of 23 compounds that cause repolarization abnormalities were positive in this assay. Antisense "knockdown" of the zebrafish KCNH2 ortholog yielded bradycardia in a dose dependent manner confirming the effects of reduction of repolarizing potassium current in this model. Classical drug-drug interactions between erythromycin and cisapride, as well as cimetidine and terfenadine, were also reproduced. This simple high-throughput assay is a promising addition to the repertoire of preclinical tests for drug-induced repolarization abnormalities. The genetic tractability of the zebrafish will allow the exploration of heritable modifiers of such drug effects.
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              Polymorphisms of KDR gene are associated with coronary heart disease.

              Our purpose was to determine whether the common polymorphisms (SNP-604, SNP1192, and SNP1719) in KDR are associated with risk of coronary heart disease. Vascular endothelial growth factor (VEGF) and its receptor KDR (kinase insert domain-containing receptor/fetal liver kinase-1, also called VEGFR2) play critical roles in angiogenesis and vascular repair, which are involved in the progress of coronary heart disease. The association of the 3 polymorphisms with risk of coronary heart disease was determined in 2 independent case-control studies: one comprised of 665 patients with coronary heart disease and 1,015 control subjects, and the other comprised of 369 patients and 625 control subjects. The SNP functions of KDR gene were studied by using luciferase reporter assays, determination of serum levels of KDR, and ligand-binding assays. The 2 independent population studies showed that the 3 polymorphisms were associated with risk of coronary heart disease with odds ratios of 1.37 for SNP-604 (p = 0.006), 1.41 for SNP1192 (p = 0.011), and 1.37 for SNP1719 (p = 0.007) in the first population, and 1.40 for SNP-604 (p = 0.015), 1.75 for SNP1192 (p = 0.003), and 1.50 for SNP1719 (p = 0.010) in the second population. The SNP-604C-bearing KDR promoter exhibited 68% of lower transcription activity than the SNP-604T-bearing promoter. The SNP1192 and SNP1719 could obviously influence the efficiency of VEGF binding to KDR. The KDR polymorphisms may serve as novel genetic markers for the risk of coronary heart disease.

                Author and article information

                Mediators Inflamm
                Mediators Inflamm
                Mediators of Inflammation
                24 April 2023
                : 2023
                : 1958046
                1Department of Cardiovascular Disease, The Second Affiliated Hospital of Shanxi Medical University, Taiyuan, Shanxi 030001, China
                2Department of Cardiovascular Disease, Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai 200433, China
                3Department of Cardiovascular Disease, Changhai Hospital Affiliated to The Second Military Medical University, Shanghai 200433, China
                Author notes

                Academic Editor: Md Sayed Ali Sheikh

                Author information
                Copyright © 2023 Hui Lv et al.

                This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                : 20 June 2022
                : 16 September 2022
                : 24 September 2022
                Funded by: Department of Cardiovascular Diseases of Changhai Hospital
                Research Article



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