Block of Mevalonate Pathway Causes Cardiovascular Failure in Zebrafish Embryos by Reducing CoQ10 Synthesis (A) Wild-type (WT) embryos at 72 hpf treated from 54 hpf with statin (mevastatin) or DMSO. Statin treatments induce a bar -like phenotype which is characterized by hemorrhages (asterisk) and heart failure (arrowhead). Scale bar, 300 μm. (B) Three dimensional projections of trunk vessels at 72 hpf of DMSO and statin-treated zebrafish embryos. Statin treatments induce specific endothelial vessels regression and fragmentation in DA and Se (arrows). Scale bar, 100 μm. (C) Quantification of bar -like phenotype after statin treatments. MEV, mevastatin 500 nM; SIM, simvastatin 500 nM; MEN, mevinolin 500 nM. (D and E) Levels of CoQ10 (D) and cholesterol (E) detected by HPLC-UV analyses in statin-treated embryos. (F and G) Bright-field (F) and fluorescent (G) images of Tg(kdrl:GFP) s843 ubiad1 +/+ and ubiad1 +/− embryos at 65 hpf treated with mevastatin (2.5 nM and 5 nM) from 32 to 50 hpf. Treatment with a low dose of statin caused hemorrhages (asterisks) and altered heart morphology (arrowheads) in ubiad1 +/− , but not in ubiad1 +/+ embryos. Although treatment with a low dose of statin did not induce specific alterations of the main vasculature, ubiad1 +/− embryos showed head vasculature, Se, and DA regression; scale bar, 300 μm. (H) Images of Tg(kdrl:GFP) s843 ubiad1 +/+ and ubiad1 +/− embryos trunk vasculature show thinner and collapsed Se and DA morphology in statin-treated ubiad1 +/− but not in ubiad1 +/+ embryos. Scale bar, 75 μm. (I) Penetrance of bar -like phenotype at 65 hpf after treatment with mevastatin. ubiad1 +/− embryos are significantly more sensitive to develop a bar -like phenotype than normal embryos ( ubiad1 +/+ ). (J) CoQ10 supplemented embryos show less susceptibility to statin treatments in terms of developing a bar- like phenotype as indicated by histograms showing the percentage of statin-treated embryos having bar -like phenotype after exogenous CoQ10 delivery. (K) CoQ10 supplementation before statin treatment prevents cardiac edema (arrowhead) and brain hemorrhages (asterisk) in barolo . Images of vehicle- and CoQ10-injected embryos after statin treatment. Scale bar, 300 μm. (L) Histograms show oxidative stress in embryos after statin treatment with or without CoQ10. All data are means ± SEM. ∗∗∗ p