He effect observed already at 10 nM concentration of atorvastatin (Urbich et al. 2002). That activation of Akt is recommended to be responsible for enhanced endothelial cell proliferation and survival. It may also stop the senescence and apoptosis of endothelial progenitors (Assmus et al. 2003). Greater, micromolar doses of statins might exert weak impact or no influence on Akt kinase phosphorylation (Urbich et al. 2002), even though Kureishi et al. noted that 1 M concentration of simvastatin enhanced Akt phosphorylation in HUVECs, the impact claimed to become accountable for inhibition of apoptosis (Kureishi et al. 2000).Europe PMC Funders Author Manuscripts Europe PMC Funders Author ManuscriptsEndothelium. Author manuscript; accessible in PMC 2006 March 13.Dulak et al.PageProangiogenic effects of statins are abolished in eNOS knockout mice (Sata et al. 2001). Interestingly, the antiangiogenic impact of atorvastatin happens at the concentrations which improve the expression of eNOS (this study and Assmus et al. 2003), the important gene involved within the angiogenic activity of endothelial cells. Furthermore, NO generation is enhanced in endothelial cells stimulated with VEGF and endothelial cell migration relies on NO synthesis (Jozkowicz et al. 2004).Europe PMC Funders Author Manuscripts Europe PMC Funders Author ManuscriptsNO protects endothelial cells from apoptosis induced by a number of stimuli, which include tumor necrosis aspect alpha (TNF)or serum withdrawal (for any review see Dimmeler and Zeiher 1999). Comparable effect is exerted by VEGF (to get a review see: Zachary and Gliki 2001). Nevertheless, induction of eNOS expression by micromolar concentration of statin seems to be not adequate to enhance the angiogenesis. HO-1 can be a stress-inducible enzyme that degrades heme to carbon monoxide, iron, and biliverdin (for overview see Sikorski et al. 2004). Besides removal of pro-oxidant heme, the items of HO-1 activity have already been recently demonstrated to become involved in many MMP-2 drug protective processes. In vascular method HO-1 expression is proangiogenic (Deramaudt et al. 1998; Dulak et al. 2002, 2004). CO, biliverdin, and its derivative, bilirubin, too as ferritin induced by iron are regarded as protective, and their influence may perhaps outcome, among other people, in prevention of endothelial cells from apoptosis (for critiques see Dulak and Jozkowicz 2003; Dulak et al. 2004). Therefore, it was reasonable to decide the prospective effect of statins on HO-1 expression. However, in our hands atorvastatin at wide array of concentrations tested didn’t have an effect on substantially HO-1 synthesis. Interestingly, HO-1 mRNA expression has been enhanced by micromolar concentrations of atorvastatin, whereas the protein production didn’t adjust. To that extent our final results are in partial agreement having a current study that demonstrated the induction of HO-1 mRNA and protein expression by simvastatin in vascular smooth muscle cells but not endothelial cells nor macrophages (Lee et al. 2004). Thus, the effect of statins might be PDGFR site cell-type dependent, but additional research are important for greater understanding of those interactions. Furthermore, antiangiogenic effects of atorvastatin at micromolar concentrations can derive from other pathways which are impacted by this compound. In our hands atorvastatin decreased uPA synthesis and IL-8 production. Certainly, uPA activity is essential for the VEGF-induced angiogenesis and in animals devoid of uPA gene angiogenesis was significantly impaired in comparison towards the wild-t.
