Description: Aims The roles of peroxisome proliferator-activated receptor (PPAR)- in vascular biology are mainly unknown. We investigated the effects of PPAR - activation on the paracrine networks between endothelial progenitor cells (EPCs) and endothelial cells (ECs)/skeletal muscle. Methods and results Treatment of EPCs with GW501516, a PPAR- agonist, induced specifically matrix metallo-proteinase (MMP)-9 by direct transcriptional activation. Subsequently, this increased-MMP-9 broke down insulin-like growth factor-binding protein (IGFBP)-3, resulting in IGF-1 receptor (IGF-1R) activation in surrounding target cells. Treatment of conditioned medium from GW501516-stimulated EPCs enhanced the number and functions of human umbilical vein ECs and C2C12 myoblasts via MMP-9-mediated IGF-1R activation. Systemic administration of GW501516 in mice increased MMP-9 expression in EPCs, and augmented IGFBP-3 degradation in serum. In a mouse hindlimb ischaemia model, systemic treatment of GW501516 or local transplantation of GW501516-treated EPCs induced IGF-1R phosphorylation in ECs and skeletal muscle in the ischaemic limbs, leading to augmented angiogenesis and skeletal muscle regeneration. It also enhanced wound healing with increased angiogenesis in a mouse skin punch wound model. These pro-angiogenic and muscle-regenerating effects were abolished by MMP-9 knock-out. Conclusion Our results suggest that PPAR- is a crucial modulator of angio-myogenesis via the paracrine effects of EPCs, and its agonist is a good candidate as a therapeutic drug for patients with peripheral vascular diseases.

Description: Background The aim of this study was to compare the safety and efficacy of biodegradable-polymer (BP) drug-eluting stents (DES), bare metal stents (BMS), and durable-polymer DES in patients undergoing coronary revascularization, we performed a systematic review and network meta-analysis using a Bayesian framework. Methods and results Study stents included BMS, paclitaxel-eluting (PES), sirolimus-eluting (SES), endeavor zotarolimus-eluting (ZES-E), cobalt–chromium everolimus-eluting (CoCr-EES), platinium–chromium everolimus-eluting (PtCr-EES), resolute zotarolimus-eluting (ZES-R), and BP biolimus-eluting stents (BP-BES). After a systematic electronic search, 113 trials with 90 584 patients were selected. The principal endpoint was definite or probable stent thrombosis (ST) defined according to the Academic Research Consortium within 1 year. Results Biodegradable polymer-biolimus-eluting stents [OR, 0.56; 95% credible interval (CrI), 0.33–0.90], SES (OR, 0.53; 95% CrI, 0.38–0.73), CoCr-EES (OR, 0.34; 95% CrI, 0.23–0.52), and PtCr-EES (OR, 0.31; 95% CrI, 0.10–0.90) were all superior to BMS in terms of definite or probable ST within 1 year. Cobalt–chromium everolimus-eluting stents demonstrated the lowest risk of ST of all stents at all times after stent implantation. Biodegradable polymer-biolimus-eluting stents was associated with a higher risk of definite or probable ST than CoCr-EES (OR, 1.72; 95% CrI, 1.04–2.98). All DES reduced the need for repeat revascularization, and all but PES reduced the risk of myocardial infarction compared with BMS. Conclusions All DESs but PES and ZES-E were superior to BMS in terms of ST within 1 year. Cobalt–chromium everolimus-eluting stents was safer than any DES even including BP-BES. Our results suggest that not only the biodegradability of polymer, but the optimal combination of stent alloy, design, strut thickness, polymer, and drug all combined determine the safety of DES.