364 research outputs found
Erratum: The histone demethylase JMJD2B regulates endothelial-to-mesenchymal transition (Proceedings of the National Academy of Sciences of the United States of America (2020) 117 (4180-4187) DOI: 10.1073/pnas.1913481117)
No full textCorrection for “The histone demethylase JMJD2B regulates endothelial-to-mesenchymal transition,” by Simone F. Glaser, Andreas W. Heumüller, Lukas Tombor, Patrick Hofmann, Marion Muhly-Reinholz, Ariane Fischer, Stefan Günther, Karoline E. Kokot, David Hassel, Sandeep Kumar, Hanjoong Jo, Reinier A. Boon, Wesley Abplanalp, David John, Jes-Niels Boeckel, and Stefanie Dimmeler, which was first published February 7, 2020; 10.1073/pnas.1913481117 (Proc. Natl. Acad. Sci. U.S.A. 117, 4180-4187). The authors note that Hitoshi Okada should be added to the author list between Karoline E. Kokot and David Hassel. Hitoshi Okada should be credited with providing mice. The corrected author line, affiliation line, and author contributions appear below. The online version has been corrected
Incorporation of recombinant fibronectin into genetically engineered elastin-based polymers
No full textCardiovascular disease is the main cause of death in the United States. Many of these conditions require the grafting or bypassing of compromised blood vessels. To this effect, biological vascular grafts (autografts and allografts) are the first line of action. However, when the patient lacks vasculature suitable for grafting use, several synthetic grafting options are available. The search for an inert biomaterial for vascular grafts has proven to be unsuccessful. This makes the interaction taking place on the blood-biomaterial interface critical for the success of the grafts.
This thesis introduces a new bio-inspired approach to tackle the mechanical and biological challenges of vascular material design. The hypothesis of this research is that recombinant fibronectin protein can be stably incorporated onto elastin-mimetic polymers to increase endothelialization. Recombinant elastin, designed to recreate the mechanical properties of natural elastin as a candidate material for vascular graft fabrication, was used as a model surface.
Recombinant fibronectin-functionalized elastin-mimetic polymer displayed significant improvement in cell adhesion. Quantification of surface bound recombinant fibronectin verified the concentration dependence of this cell adhesive behavior. Modified elastin-mimetic polymer also demonstrated an enhanced ability to support endothelial cell proliferation. Furthermore, the stability of recombinant fibronectin-modified polymers was assessed. These studies provide the foundation for fabricating elastin-mimetic vascular grafts with improved endothelialization and subsequent biological performance.M.S
Medical School Watercooler Newsletter - March 30, 2014
No full textThis is the March 30, 2014 edition of the Frederick P. Whiddon College of Medicine\u27s newsletter - Watercooler.
Contents Include: USA Health System Offers Free Skin Cancer Screenings USA Pediatric Endocrinology Clinic Certified in Diabetes Education Recognition Program USA Surgery Hosts Greater Gulf Coast Trauma and Acute Care Surgery Symposium April 10 DSS to Feature Dr. Hanjoong Jo Dr. Al-Mehdi Receives Pharmacology Travel Awar
Regulation of endothelial gene transcription by shear stress in a manner dependent on p47phox-based NADPH oxidases
No full textAtherosclerosis occurs preferentially at branches and curves in arteries exposed to disturbed flow while sparing straight portions of arteries exposed to undisturbed flow. In vivo and in vitro studies have implicated NADPH oxidases in atherosclerosis and hypertension. Shear stress can induce reactive oxygen species production in endothelial cells from a variety of sources, including NADPH oxidases. Here, we examined the hypothesis that unidirectional laminar shear (LS) and oscillatory shear (OS) would differentially regulate gene expression profiles in NADPH oxidase-dependent and -independent manners, and that these genes would provide novel molecular targets in understanding endothelial cell biology and vascular disease.
The p47phox subunit of the NADPH oxidase can be an important regulator of certain Nox isoforms, including Nox1 and Nox2 which may be responsible for shear-induced superoxide production. In order to isolate p47phox-dependent shear responses, we took advantage of the p47phox-/- transgenic mouse model which lacks a functional p47phox subunit. We developed a method to isolate murine aortic endothelial cells using an enzymatic digestion technique. These cells expressed characteristic endothelial markers, including VE-cadherin, PECAM1, and eNOS, and aligned in the direction of flow. We successfully isolated primary murine aortic endothelial cells from both wild-type C57BL/6 mice (MAE-WT) and p47phox-/- mice (MAE-p47). Furthermore, we established an immortalized cell line from each of these cell types, iMAE-WT and iMAE-p47.
We carried out microarray studies using Affymetrix Mouse Genome 430 2.0 Arrays (39,000+ transcripts) on MAE-WT and MAE-p47 that were exposed to atheroprotective LS or atherogenic OS for 24 hours. In comparison to LS, OS significantly changed the expression of 187 and 298 genes in MAE-WT and MAE-p47, respectively. Of those, 23 genes showed similar gene expression patterns in both cell types while 462 genes showed different gene expression patterns in the two cell types, demonstrating a considerable role for p47phox-based NADPH oxidases in shear-dependent gene expression. Changes in expression of several genes, including Kruppel-like factor 2 (Klf2), endothelial nitric oxide synthase (eNOS), angiopoietin 2 (Ang2), junctional adhesion molecule 2 (Jam2), bone morphogenic receptor type II (Bmpr2), and bone morphogenic protein 4 (Bmp4) were confirmed by quantitative PCR and/or immunoblotting using both primary cells and immortalized cells. Of these genes, our data suggest that Jam2, Bmpr2, and Bmp4 may be shear-sensitive in a p47phox-dependent manner. Taken together, our studies have identified a set of shear- and p47phox-sensitive genes, including unexpected and novel targets, which may play critical roles in vascular cell biology and pathobiology.Ph.D
Endothelial bone morphogenic protein 4 and bone morphogenic protein receptor II expression in inflammation and atherosclerosis
No full textAtherosclerosis is an inflammatory disease, occurring preferentially in arterial regions with disturbed flow. We have shown that disturbed flow induces inflammation in endothelial cells (ECs) by producing bone morphogenic protein-4 (BMP4). Moreover, chronic BMP4 infusion induces endothelial dysfunction and systemic hypertension in mice. Here, we examined which BMP receptors (BMPR) mediate BMP4 action in ECs. Western blot, immunostaining and RT-PCR studies using human and bovine ECs, mouse aortas and human coronary arteries (HCA) showed that BMPRI (ALK2 and 6) and BMP-RII were expressed in ECs. As a functional test, ECs were treated with a BMPRII siRNA to knockdown expression. BMPRII knockdown blocked a well-known BMP4 response - smad1/5/8 phosphorylation, as expected. Unexpectedly, BMPRII knockdown itself significantly stimulated ICAM-1 and VCAM-1 expression and monocyte adhesion in a BMP4-independent manner. Inflammatory responses caused by BMPRII knockdown were blocked by inhibitors of NADPH oxidase and NFκ B. From these results, we hypothesized that BMP-RII knockdown in ECs would cause inflammation, which is a critical event in atherosclerosis initiation and progression. Genetic mutations of BMPRII have been linked to primary pulmonary hypertension. However, it is not known whether BMP-RII is regulated by atherosclerotic conditions and plays a role in non-pulmonary vessels causing inflammation and atherosclerosis. We examined BMPRII levels in HCA by immunostaining. While non-diseased arteries showed intense staining of BMPRII, the expression decreased as lesions became more advanced. BMPRII was virtually undetectable in the most advanced lesions. These findings suggested a potential link between pro-atherosclerotic conditions and BMP-RII levels. We tested this hypothesis by treating ECs with pro-inflammatory cytokines found in atheromas: TNFα decreased BMPRII by 2-fold. In contrast, statins increased BMPRII by 4-fold. In summary, we demonstrate for the first time that BMPRII can be down- or up-regulated by pro- or anti-atherogenic conditions, respectively, and it is dramatically decreased in HCA with advanced plaques. Moreover, BMPRII knockdown in ECs induces inflammation, a critical atherogenic step. We propose that focal inflammation initiated by disturbed flow, together with circulating pro-atherogenic risk factors, may lead to a vicious cycle of BMPRII down-regulation causing secondary inflammation and atheroma progression.Ph.D
Shear stress regulates endothelial NO synthase (eNOS) by the protein kinase A (PKA)-dependent mechanisms
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