Biyashev D.,Northwestern University |
Biyashev D.,Feinberg Cardiovascular Research Institute |
Veliceasa D.,Northwestern University |
Topczewski J.,Northwestern University |
And 8 more authors.
Blood | Year: 2012
We discovered that miR-27b controls 2 critical vascular functions: it turns the angiogenic switch on by promoting endothelial tip cell fate and sprouting and it promotes venous differentiation.We have identified its targets, a Notch ligand Deltalike ligand 4 (Dll4) and Sprouty homologue 2 (Spry2). miR-27b knockdown in zebrafish and mouse tissues severely impaired vessel sprouting and filopodia formation. Moreover, miR-27b was necessary for the formation of the first embryonic vein in fish and controlled the expression of arterial and venous markers in human endothelium, including Ephrin B2 (EphB2), EphB4, FMS-related tyrosine kinase 1 (Flt1), and Flt4. In zebrafish, Dll4 inhibition caused increased sprouting and longer intersegmental vessels and exacerbated tip cell migration. Blocking Spry2 caused premature vessel branching. In contrast, Spry2 overexpression eliminated the tip cell branching in the intersegmental vessels. Blockade of Dll4 and Spry2 disrupted arterial specification and augmented the expression of venous markers. Blocking either Spry2 or Dll4 rescued the miR-27b knockdown phenotype in zebrafish and in mouse vascular explants, pointing to essential roles of these targets downstream of miR-27b. Our study identifies critical role of miR-27b in the control of endothelial tip cell fate, branching, and venous specification and determines Spry2 and Dll4 as its essential targets. © 2012 by The American Society of Hematology.
Zhou X.,Tianjin University |
Liu X.-L.,Tianjin University |
Ji W.-J.,Tianjin University |
Liu J.-X.,Tianjin University |
And 14 more authors.
Medicine (United States) | Year: 2016
In experimental myocardial infarction (MI), a rise in cell counts of circulating monocyte subsets contributes to impaired myocardial healing and to atherosclerotic plaque destabilization. In humans, the prognostic role of monocyte subsets in patients suffering STelevation MI (STEMI) is still unclear. In the present study, we aimed to determine the kinetics of the 3 monocyte subsets (classical CD14CD16-, intermediate CD14CD16, and nonclassical CD14CD16 monocytes), as well as the subset-specific monocyte-platelet aggregates (MPA), in acute STEMI followed by primary percutaneous coronary intervention (PCI), and their relationships with cardiovascular outcomes during a 2-year follow-up. Monocyte subsets and MPA were measured in 100 STEMI patients receiving primary PCI on days 1, 2, 3, 5, and 7 of symptom onset, which were compared with 60 stable coronary heart disease patients and 35 healthy volunteers. From day 1 to day 7, significant increases in the counts of CD14CD16 monocytes and CD14CD16 MPA were observed, with peak levels on day 2. During a median followup of 2.0 years, 28 first cardiovascular events (defined as cardiovascular death, nonfatal ischemic stroke, recurrent MI, need for emergency or repeat revascularization, and rehospitalization for heart failure) were recorded. After adjustment for confounders, CD14CD16 monocytosis (day 1 [HR: 3.428; 95% CI: 1.597-7.358; P=0.002], day 2 [HR: 4.835; 95% CI: 1.106-21.13; P=0.04], day 3 [HR: 2.734; 95% CI: 1.138-6.564; P=0.02], and day 7 [HR: 2.647; 95% CI: 1.196-5.861; P=0.02]), as well as increased levels of CD14CD16 MPA measured on all time points (days 1, 2, 3, 5, and 7), had predictive values for adverse cardiovascular events. In conclusion, our data show the expansion of the CD14CD16 monocyte subset during acute phase of STEMI has predictive values for 2-year adverse cardiovascular outcomes in patients treated with primary PCI. Future studies will be warranted to elucidate whether CD14CD16 monocytes may become a target cell population for new therapeutic strategies after STEMI. Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved.
Kannan Mutharasan R.,Feinberg Cardiovascular Research Institute |
Foit L.,Northwestern University |
Shad Thaxton C.,Northwestern University
Journal of Materials Chemistry B | Year: 2015
High-density lipoproteins (HDL) are a class of natural nanostructures found in the blood and are composed of lipids, proteins, and nucleic acids (e.g. microRNA). Their size, which appears to be well-suited for both tissue penetration/retention as well as payload delivery, long circulation half-life, avoidance of endosomal sequestration, and potential low toxicity are all excellent properties to model in a drug delivery vehicle. In this review, we consider high-density lipoproteins for therapeutic delivery systems. First we discuss the structure and function of natural HDL, describing in detail its biogenesis and transformation from immature, discoidal forms, to more mature, spherical forms. Next we consider features of HDL making them suitable vehicles for drug delivery. We then describe the use of natural HDL, discoidal HDL analogs, and spherical HDL analogs to deliver various classes of drugs, including small molecules, lipids, and oligonucleotides. We briefly consider the notion that the drug delivery vehicles themselves are therapeutic, constituting entities that exhibit "theralivery." Finally, we discuss challenges and future directions in the field. © The Royal Society of Chemistry 2016.
Naillat F.,University of Oulu |
Naillat F.,Babraham Institute |
Yan W.,Soochow University of China |
Karjalainen R.,Institute for Molecular Medicine |
And 8 more authors.
Experimental Cell Research | Year: 2015
The indifferent mammalian embryonic gonad generates an ovary or testis, but the factors involved are still poorly known. The Wnt-4 signal represents one critical female determinant, since its absence leads to partial female-to-male sex reversal in mouse, but its signalling is as well implicated in the testis development. We used the Wnt-4 deficient mouse as a model to identify candidate gonadogenesis genes, and found that the Notum, Phlda2, Runx-1 and Msx1 genes are typical of the wild-type ovary and the Osr2, Dach2, Pitx2 and Tacr3 genes of the testis. Strikingly, the expression of these latter genes becomes reversed in the Wnt-4 knock-out ovary, suggesting a role in ovarian development. We identified the transcription factor Runx-1 as a Wnt-4 signalling target gene, since it is expressed in the ovary and is reduced upon Wnt-4 knock-out. Consistent with this, introduction of the Wnt-4 signal into early ovary cells ex vivo induces Runx-1 expression, while conversely Wnt-4 expression is down-regulated in the absence of Runx-1. We conclude that the Runx-1 gene can be a Wnt-4 signalling target, and that Runx-1 and Wnt-4 are mutually interdependent in their expression. The changes in gene expression due to the absence of Wnt-4 in gonads reflect the sexually dimorphic role of this signal and its complex gene network in mammalian gonad development. © 2015 The Authors.
Shah A.,University of Toronto |
Shah A.,Toronto General Research Institute |
Xia L.,University of Toronto |
Xia L.,Toronto General Research Institute |
And 12 more authors.
Journal of the American Society of Nephrology | Year: 2015
Expression of thioredoxin-interacting protein (TxNIP), an endogenous inhibitor of the thiol oxidoreductase thioredoxin, is augmented by high glucose (HG) and promotes oxidative stress.We previously reported that TxNIP-deficient mesangial cells showed protection from HG-induced reactive oxygen species, mitogenactivated protein kinase phosphorylation, and collagen expression.Here,we investigated the potential roleof TxNIP in the pathogenesis of diabetic nephropathy (DN) in vivo. Wild-type (WT) control, TxNIP-/-, and TxNIP+/- mice were rendered equally diabetic with low-dose streptozotocin. In contrast to effects in WT mice, diabetes did not increase albuminuria, proteinuria, serum cystatin C, or serum creatinine levels in TxNIP-/- mice.Whereas morphometric studies of kidneys revealed a thickened glomerular basement membrane and effaced podocytes in the diabetic WT mice, these changes were absent in the diabetic TxNIP-/-mice. Immunohistochemical analysis revealed significant increases in the levels of glomerular TGF-β1, collagen IV, and fibrosis only inWTdiabeticmice. Additionally, onlyWTdiabeticmice showed significant increases in oxidative stress (nitrotyrosine, urinary 8-hydroxy-2-deoxy-guanosine) and inflammation (IL-1bmRNA, F4/80 immunohistochemistry). Expression levels ofNox4-encodedmRNA and protein increased only in the diabetic WT animals. A significant loss of podocytes, assessed by Wilms' tumor 1 and nephrin staining and urinary nephrin concentration, was found in diabetic WT but not TxNIP-/- mice. Furthermore, in cultured human podocytes exposed to HG, TxNIP knockdown with siRNA abolished the increased mitochondrial O2 2 generation and apoptosis. These data indicate that TxNIP has a critical role in the progression ofDNandmay be a promising therapeutic target. Copyright © 2015 by the American Society of Nephrology.