31 research outputs found
Splenic Ly6C(hi) monocytes contribute to adverse late post-ischemic left ventricular remodeling in heme oxygenase-1 deficient mice
No evidence for differential survival or predation between sympatric color morphs of an aposematic poison frog
A new class of glycomimetic drugs to prevent free fatty acid-induced endothelial dysfunction
Background: Carbohydrates play a major role in cell signaling in many biological processes. We have developed a set of glycomimetic drugs that mimic the structure of carbohydrates and represent a novel source of therapeutics for endothelial dysfunction, a key initiating factor in cardiovascular complications. Purpose: Our objective was to determine the protective effects of small molecule glycomimetics against free fatty acidinduced endothelial dysfunction, focusing on nitric oxide (NO) and oxidative stress pathways. Methods: Four glycomimetics were synthesized by the stepwise transformation of 2,5dihydroxybenzoic acid to a range of 2,5substituted benzoic acid derivatives, incorporating the key sulfate groups to mimic the interactions of heparan sulfate. Endothelial function was assessed using acetylcholineinduced, endotheliumdependent relaxation in mouse thoracic aortic rings using wire myography. Human umbilical vein endothelial cell (HUVEC) behavior was evaluated in the presence or absence of the free fatty acid, palmitate, with or without glycomimetics (1µM). DAF2 and H2DCFDA assays were used to determine nitric oxide (NO) and reactive oxygen species (ROS) production, respectively. Lipid peroxidation colorimetric and antioxidant enzyme activity assays were also carried out. RTPCR and western blotting were utilized to measure Akt, eNOS, Nrf2, NQO1 and HO1 expression. Results: Ex vivo endotheliumdependent relaxation was significantly improved by the glycomimetics under palmitateinduced oxidative stress. In vitro studies showed that the glycomimetics protected HUVECs against the palmitateinduced oxidative stress and enhanced NO production. We demonstrate that the protective effects of preincubation with glycomimetics occurred via upregulation of Akt/eNOS signaling, activation of the Nrf2/ARE pathway, and suppression of ROSinduced lipid peroxidation. Conclusion: We have developed a novel set of small molecule glycomimetics that protect against free fatty acidinduced endothelial dysfunction and thus, represent a new category of therapeutic drugs to target endothelial damage, the first line of defense against cardiovascular disease
Stromal cell–derived factor 1 promotes angiogenesis via a heme oxygenase 1–dependent mechanism
The effect of metapopulation dynamics on the survival and spread of a novel, conspicuous prey
PPAR\gamma activation but not PPAR\gamma haplodeficiency affects proangiogenic potential of endothelial cells and bone marrow-derived progenitors
Background. Peroxisome proliferator-activated receptor-? (PPAR?) agonists, which have been used as insulin sensitizers in diabetic patients, may improve functions of endothelial cells (ECs). We investigated the effect of PPAR? on angiogenic activities of murine ECs and bone marrow-derived proangiogenic cells (PACs). Methods. PACs were isolated from bone marrow of 10¿12 weeks old, wild type, db/db and PPAR? heterozygous animals. Cells were cultured on fibronectin and gelatin coated dishes in EGM-2MV medium. For in vitro stimulations, rosiglitazone (10 ?mol/L) or GW9662 (10 ?mol/L) were added to 80% confluent cell cultures for 24 hours. Angiogenic potential of PACs and ECs was tested in vitro and in vivo in wound healing assay and hind limb ischemia model. Results. ECs and PACs isolated from diabetic db/db mice displayed a reduced angiogenic potential in ex vivo and in vitro assays, the effect partially rescued by incubation of cells with rosiglitazone (PPAR? activator). Correction of diabetes by administration of rosiglitazone in vivo did not improve angiogenic potential of isolated PACs or ECs. In a hind limb ischemia model we demonstrated that local injection of conditioned media harvested from wild type PACs improved the blood flow restoration in db/db mice, confirming the importance of paracrine action of the bone marrow-derived cells. Transcriptome analysis showed an upregulation of prooxidative and proinflammatory pathways, and downregulation of several proangiogenic genes in db/db PACs. Interestingly, db/db PACs had also a decreased level of PPAR? and changed expression of PPAR?-regulated genes. Using normoglycemic PPAR?+/? mice we demonstrated that reduced expression of PPAR? does not influence neovascularization either in wound healing or in hind limb ischemia models. Conclusions. In summary, activation of PPAR? by rosiglitazone improves angiogenic potential of diabetic ECs and PACs, but decreased expression of PPAR? in diabetes does not impair angiogenesis