Heme oxygenase-1 is required for angiogenic function of bone marrow-derived progenitor cells : role in therapeutic revascularization

Aims: Heme oxygenase-1 (HO-1) is a cytoprotective enzyme that can be down-regulated in diabetes. Its importance for mature endothelium has been described, but its role in proangiogenic progenitors is not well known. We investigated the effect of HO-1 on the angiogenic potential of bone marrow-derived cells (BMDCs) and on blood flow recovery in ischemic muscle of diabetic mice. Results: Lack of HO-1 decreased the number of endothelial progenitor cells (Lin−CD45−cKit-Sca-1+VEGFR-2+) in murine bone marrow, and inhibited the angiogenic potential of cultured BMDCs, affecting their survival under oxidative stress, proliferation, migration, formation of capillaries, and paracrine proangiogenic potential. Transcriptome analysis of HO-1−/− BMDCs revealed the attenuated up-regulation of proangiogenic genes in response to hypoxia. Heterozygous HO-1+/− diabetic mice subjected to hind limb ischemia exhibited reduced local expression of vascular endothelial growth factor (VEGF), placental growth factor (PlGF), stromal cell-derived factor 1 (SDF-1), VEGFR-1, VEGFR-2, and CXCR-4. This was accompanied by impaired revascularization of ischemic muscle, despite a strong mobilization of bone marrow-derived proangiogenic progenitors (Sca-1+CXCR-4+) into peripheral blood. Blood flow recovery could be rescued by local injections of conditioned media harvested from BMDCs, but not by an injection of cultured BMDCs. Innovation: This is the first report showing that HO-1 haploinsufficiency impairs tissue revascularization in diabetes and that proangiogenic in situ response, not progenitor cell mobilization, is important for blood flow recovery. Conclusions: HO-1 is necessary for a proper proangiogenic function of BMDCs. A low level of HO-1 in hyperglycemic mice decreases restoration of perfusion in ischemic muscle, which can be rescued by a local injection of conditioned media from cultured BMDCs

Laparoscopic gastrectomy with enhanced recovery after surgery protocol : single-center experience

BACKGROUND: Surgery remains the mainstay of gastric cancer treatment. It is, however, associated with a relatively high risk of perioperative complications. The use of laparoscopy and the Enhanced Recovery After Surgery (ERAS) protocol allows clinicians to limit surgically induced trauma, thus improving recovery and reducing the number of complications. The aim of the study is to present clinical outcomes of patients with gastric cancer undergoing laparoscopic gastrectomy combined with the ERAS protocol. MATERIAL/METHODS: Fifty-three (21 female/32 male) patients who underwent elective laparoscopic total gastrectomy due to cancer were prospectively analyzed. Demographic and surgical parameters were assessed, as well as the compliance with ERAS protocol elements, length of hospital stay, number of complications, and readmissions. RESULTS: Mean operative time was 296.4±98.9 min, and mean blood loss was 293.3±213.8 mL. In 3 (5.7%) cases, conversion was required. Median length of hospital stay was 5 days. Compliance with ERAS protocol was 79.6±14.5%. Thirty (56.6%) patients tolerated an early oral diet well within 24 h postoperatively; in 48 (90.6%) patients, mobilization in the first 24 hours was successful. In 17 (32.1%) patients, postoperative complications occurred, with 7 of them (13.2%) being serious (Clavien-Dindo 3-5). The 30-day readmission rate was 9.4%. CONCLUSIONS: The combination of laparoscopy and the ERAS protocol in patients with gastric cancer is feasible and allows achieving good clinical outcomes

Nrf2 regulates angiogenesis : effect on endothelial cells, bone marrow-derived proangiogenic cells and hind limb ischemia

Aims: Nuclear factor E2-related factor 2 (Nrf2), a key cytoprotective transcription factor, regulates also proangiogenic mediators, interleukin-8 and heme oxygenase-1 (HO-1). However, hitherto its role in blood vessel formation was modestly examined. Particularly, although Nrf2 was shown to affect hematopoietic stem cells, it was not tested in bone marrow-derived proangiogenic cells (PACs). Here we investigated angiogenic properties of Nrf2 in PACs, endothelial cells, and inflammation-related revascularization. Results: Treatment of endothelial cells with angiogenic cytokines increased nuclear localization of Nrf2 and induced expression of HO-1. Nrf2 activation stimulated a tube network formation, while its inhibition decreased angiogenic response of human endothelial cells, the latter effect reversed by overexpression of HO-1. Moreover, lack of Nrf2 attenuated survival, proliferation, migration, and angiogenic potential of murine PACs and affected angiogenic transcriptome in vitro. Additionally, angiogenic capacity of PAC Nrf2(−/−) in in vivo Matrigel assay and PAC mobilization in response to hind limb ischemia of Nrf2(−/−) mice were impaired. Despite that, restoration of blood flow in Nrf2-deficient ischemic muscles was better and accompanied by increased oxidative stress and inflammatory response. Accordingly, the anti-inflammatory agent etodolac tended to diminish blood flow in the Nrf2(−/−) mice. Innovation: Identification of a novel role of Nrf2 in angiogenic signaling of endothelial cells and PACs. Conclusion: Nrf2 contributes to angiogenic potential of both endothelial cells and PACs; however, its deficiency increases muscle blood flow under tissue ischemia. This might suggest a proangiogenic role of inflammation in the absence of Nrf2 in vivo, concomitantly undermining the role of PACs in such conditions. Antioxid. Redox Signal. 20, 1693–1708