Proposed scheme for endothelial eNOS and AMPK activation by telmisartan.

<p>Telmisartan activates eNOS and increases NO production via p38 MAPK, which is independent of AT1R.</p

Telmisartan-induced eNOS phosphorylation levels after pretreatment with PI3K or PKA inhibitors.

<p><b>A</b>. HUVECs were incubated with the vehicle (DMSO) or telmisartan for 2 h after pretreatment with PI3K inhibitors wortmannin (1 µM) or LY294002 (50 µM) for 30 min. <b>B</b>. Relative phosphorylation levels of eNOS calculated as the ratio of phospho-eNOS to total eNOS. Bar graph shows the mean ± SEM of 4 independent experiments. Wort, wortmannin; LY, LY294002. *, p < 0.05 versus control (nc+DMSO); #, p < 0.05 versus Wort+DMSO; †, p < 0.05 versus LY+DMSO. <b>C</b>. HUVECs were incubated with the vehicle (DMSO) or telmisartan for 2 h after pretreatment with PKA inhibitors KT5720 (5 µM) or H89 (10 µM) for 30 min. <b>D</b>. Relative phosphorylation levels of eNOS calculated as the ratio of phospho-eNOS to total eNOS. Bar graph shows the mean ± SEM of 4 independent experiments. KT, KT5720. *, p < 0.05 versus control (nc+DMSO); #, p < 0.05 versus KT+DMSO; †, p < 0.05 versus H89+DMSO.</p

AT1 inhibition does not inhibit eNOS or AMPK phosphorylation induced by telmisartan in HUVECs.

<p><b>A</b>. HUVECs were incubated with the vehicle (DMSO) or telmisartan for 2 h under the conditions, in which the AT1R binding pocket was blocked by pretreatment with high concentrations of valsartan (200 µM) for 30 min. Representative immunoblots of eNOS and AMPK are shown. <b>B</b>. Relative phosphorylation levels of eNOS were calculated as the band intensity ratio of phospho-eNOS to total eNOS. Bar graph shows the mean ± SEM of 4 independent experiments. <b>C</b>. Relative phosphorylation levels of AMPK were calculated as the band intensity ratio of phospho-AMPK to total AMPK. Bar graph shows the mean ± SEM of 4 independent experiments. nc, negative control. *, p < 0.05 versus control (nc+DMSO); #, p < 0.05 versus Val+DMSO; †, p < 0.01 versus control; **, p < 0.01 versus Val+DMSO.</p

Telmisartan-induced eNOS phosphorylation levels after pretreatment with PPARγ or PPARβ/δ inhibitors.

<p><b>A</b>. HUVECs were incubated with the vehicle (DMSO) or telmisartan for 2 h after pretreatment with the PPARγ inhibitor GW9662 (10 µM) for 30 min. <b>B</b>. Relative phosphorylation levels of eNOS calculated as the ratio of phospho-eNOS to total eNOS. Bar graph shows the mean ± SEM of 4 independent experiments. GW, GW9662. *, p < 0.01 versus control (nc+DMSO); #, p < 0.01 versus GW+DMSO. <b>C</b>. HUVECs were incubated with the vehicle (DMSO) or telmisartan for 2 h after pretreatment with the PPARβ/δ inhibitor GSK3787 (10 µM) for 30 min. <b>D</b>. Relative phosphorylation levels of eNOS calculated as the ratio of phospho-eNOS to total eNOS. Bar graph shows the mean ± SEM of 4 independent experiments. GSK, GSK3787. *, p < 0.05 versus control (nc+DMSO); #, p < 0.05 versus GSK+DMSO.</p

Immunohistochemical staining of aortic endothelium treated with valsartan and telmisartan.

<p><b>A</b>. Mouse descending aortas after oral administration with valsartan (5 mg⋅kg⁻¹⋅day⁻¹) or telmisartan (2.5 mg⋅kg⁻¹⋅day⁻¹) for 7 days were immunostained using anti-phospho eNOS (Ser1177) and anti-eNOS antibodies. <b>B</b>, <b>C</b>. Staining intensities were measured in 30 randomly selected field of endothelium (E) and media (M). The intensity ratios of the endothelium to media were compared statistically.</p

Telmisartan induces p38 MAPK and CREB phosphorylation in HUVECs.

<p><b>A</b>. HUVECs were incubated with telmisartan for 15 min to 4 h to evaluate the phosphorylation levels of p38MAPK Thr180/Tyr182 and CREB Ser133. <b>B</b>. Relative phosphorylation levels of CREB calculated as the ratio of phospho-CREB (Ser133) to total CREB. Bar graph shows the mean ± SEM of 4 independent experiments. <b>C</b>. Relative phosphorylation levels of p38 MAPK calculated as the ratio of phospho-p38 MAPK to total p38 MAPK. Bar graph shows the mean ± SEM of 4 independent experiments. <b>B</b>, <b>C</b>: *, p < 0.05 versus control (0 min); #, p < 0.01 versus control. <b>D</b>. HUVECs were incubated with the vehicle (DMSO) or telmisartan for 2 h under the condition of p38 MAPK inhibition by pretreatment with SB202190 (10 µM) for 30 min. <b>E</b>. Relative phosphorylation levels of eNOS calculated as the ratio of phospho-eNOS to total eNOS. Bar graph shows the mean ± SEM of 4 independent experiments. SB, SB202190. *, p < 0.01 versus control (nc+DMSO). <b>F</b>. HUVECs were incubated with the vehicle (DMSO) or telmisartan for 2 h after overexpression of dominant-negative p38 MAPK (dn p38 MAPK) or GFP by adenoviral vectors. HA-tag expression was checked to verify overexpression of dn p38 MAPK. <b>G</b>. Relative phosphorylation levels of eNOS calculated as the ratio of phospho-eNOS to total eNOS. Bar graph shows the mean ± SEM of 4 independent experiments. *, p < 0.05 versus control (GFP+DMSO).</p

Impact of the Distance from the Stent Edge to the Residual Plaque on Edge Restenosis following Everolimus-Eluting Stent Implantation

<div><p>Objectives</p><p>This study aimed to assess the relation between stent edge restenosis (SER) and the distance from the stent edge to the residual plaque using quantitative intravascular ultrasound.</p><p>Background</p><p>Although percutaneous coronary intervention with drug-eluting stents has improved SER rates, determining an appropriate stent edge landing zone can be challenging in cases of diffuse plaque lesions. It is known that edge vascular response can occur within 2 mm from the edge of a bare metal stent, but the distance to the adjacent plaque has not been evaluated for drug-eluting stents.</p><p>Methods</p><p>A total of 97 proximal residual plaque lesions (plaque burden [PB] >40%) treated with everolimus-eluting stents were retrospectively evaluated to determine the distance from the stent edge to the residual plaque.</p><p>Results</p><p>The SER group had significantly higher PB (59.1 ± 6.1% vs. 51.9 ± 9.1% for non-SER; P = 0.04). Higher PB was associated with SER, with the cutoff value of 54.74% determined using receiver operating characteristic (ROC) curve analysis. At this cutoff value of PB, the distance from the stent edge to the lesion was significantly associated with SER (odds ratio = 2.05, P = 0.035). The corresponding area under the ROC curve was 0.725, and the cutoff distance value for predicting SER was 1.0 mm.</p><p>Conclusion</p><p>An interval less than 1 mm from the proximal stent edge to the nearest point with the determined PB cutoff value of 54.74% was significantly associated with SER in patients with residual plaque lesions.</p></div

Privacy: An Issue of Priority

This note highlights the competing stakes in the online privacy debate. It provides an overview of the U.S. business model of companies that participate in data gathering and analysis, and why they do so (namely because of the emergence of Big Data technologies), and discusses examples of how online privacy has eroded in recent years, in turn highlighting the need for federal action. This note also discusses the current status quo of online privacy in America, and why current legislation is inadequate to address online privacy issues. It further includes a discussion of why the U.S. should let the new EU Directive be a guide for establishing its own comprehensive privacy protection framework, and concludes with an analysis of the most important principles that can be taken from the EU Directive. Additionally, strategies are discussed on how to incentivize companies to engage in beneficial research for the entire industry that could make the transition of complying with the new online privacy regulations more manageable

Procedural characteristics and post-stenting intravascular ultrasound (IVUS) findings.

<p>SER: stent edge restenosis.</p><p>Data are presented as mean ± SD.</p><p>Stent/Lumen ratio is the ratio of stent area to mean lumen area of the proximal reference.</p><p>Stent/Vessel ratio is the ratio of stent area to mean vessel area of the proximal reference.</p><p>P values suggesting statistical significance are shown in italics.</p><p>Procedural characteristics and post-stenting intravascular ultrasound (IVUS) findings.</p

Study flow chart.

<p>EES: everolimus-eluting stent; IVUS: Intravascular ultrasound; LMT: left main trunk; SER: stent edge restenosis;</p