scholarly journals ADAM12: a genetic modifier of preclinical peripheral arterial disease

2015 ◽  
Vol 309 (5) ◽  
pp. H790-H803 ◽  
Author(s):  
Ayotunde O. Dokun ◽  
Lingdan Chen ◽  
Mitsuharu Okutsu ◽  
Charles R. Farber ◽  
Surovi Hazarika ◽  
...  
Keyword(s):  
Peripheral Arterial Disease ◽  
Inbred Mouse ◽  
Genetic Modifier ◽  
Arterial Disease ◽  
Endothelial Cell Proliferation ◽  
Mouse Strains ◽  
Trait Locus ◽  
Peripheral Arterial

In prior studies from multiple groups, outcomes following experimental peripheral arterial disease (PAD) differed considerably across inbred mouse strains. Similarly, in humans with PAD, disease outcomes differ, even when there are similarities in risk factors, disease anatomy, arteriosclerotic burden, and hemodynamic measures. Previously, we identified a locus on mouse chromosome 7, limb salvage-associated quantitative trait locus 1 (LSq-1), which was sufficient to modify outcomes following experimental PAD. We compared expression of genes within LSq-1 in Balb/c mice, which normally show poor outcomes following experimental PAD, with that in C57Bl/6 mice, which normally show favorable outcomes, and found that a disintegrin and metalloproteinase gene 12 ( ADAM12) had the most differential expression. Augmentation of ADAM12 expression in vivo improved outcomes following experimental PAD in Balb/c mice, whereas knockdown of ADAM12 made outcomes worse in C57Bl/6 mice. In vitro, ADAM12 expression modulates endothelial cell proliferation, survival, and angiogenesis in ischemia, and this appeared to be dependent on tyrosine kinase with Ig-like and EGF-like domain 2 (Tie2) activation. ADAM12 is sufficient to modify PAD severity in mice, and this likely occurs through regulation of Tie2.

Abstract 5281: Bioluminescence Imaging of X-Ray Visible Microencapsulated Mesenchymal Stem Cells for Cell Based Therapy of Peripheral Arterial Disease

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Dorota A Kedziorek ◽  
Piotr Walczak ◽  
Yingli Fu ◽  
Nicole Azene ◽  
Aravind Arepally ◽  
...  
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Peripheral Arterial Disease ◽  
Arterial Disease ◽  
X Ray ◽  
Encapsulated Cells ◽  
X Ray Imaging ◽  
Peripheral Arterial

Introduction: Therapeutic angiogenesis in Peripheral Arterial Disease (PAD) using stem cell therapy is potentially complicated by immunorejection. To overcome this problem, microen-capsulation using the alginate-poly-L-lysine (PLL)-alginate (APA) method was developed to provide a protective porous bubble to block antibodies but allow exchange of small molecules. Recently, we have developed a method to enable X-ray detection of these capsules. However, cell survival within the capsules could not be determined. Plus PLL can be mildly cytotoxic. In the present study, we combined reporter gene methods to verify cell survival with X-ray detection of the microcapsules in a rabbit PAD model and studied the PLL impact on cell viability. Methods: Rabbit mesenchymal stem cells (MSCs) were transfected with triple fusion (TF) reporter gene for bioluminescence (firefly luciferase), fluorescence (red fluorescent protein) and PET (truncated thymidine kinase). TF-MSCs were encapsulated in the perfluorooctyl bromide (PFOB) capsules to enable computed tomographic detection. Capsule crosslinking was performed with three PLL concentrations, i.e., 0.005%, 0.025% and 0.05%. Bioluminescent imaging (BLI) was used to monitor cells survival for one week in vitro and after intramuscular injection in vivo . Results: Serial in vitro BLI enabled the detection of viable encapsulated MSCs without detrimental signal degradation (~13% decrease of BLI signal intensity after PFOB encapsulation comparing to equal number of naked MSCs). PLL did not result in cell death; higher PLL concentrations were correlated with stronger BLI signal. BLI signal production was only slightly reduced by second layer of alginate (~80% for 0.05% PLL). In vivo BLI demonstrated the detection of naked, APA, and PFOB-encapsulated TF-MSCs. X-ray imaging enabled PFOB microcapsules detection relative to vasculature. Conclusion: BLI allows monitoring of encapsulated cells survival. PLL concentrations ≤ 0.05% appear safe for encapsulated cells with higher concentration being associated with enhanced crosslinking and capsule stability. MSCs expressing TF reporter in PFOB microcapsules enables dual monitoring of cell delivery/capsule tracking by X-ray imaging and cell viability with BLI.

scholarly journals Delivery of hepatocyte growth factor mRNA from nanofibrillar scaffolds in a pig model of peripheral arterial disease

2020 ◽  
Vol 15 (6) ◽  
pp. 1761-1773
Author(s):  
Tatiana S Zaitseva ◽  
Guang Yang ◽  
Dimitris Dionyssiou ◽  
Maedeh Zamani ◽  
Steve Sawamura ◽  
...  
Keyword(s):  
Peripheral Arterial Disease ◽  
Therapeutic Potential ◽  
Arterial Disease ◽  
Translational Efficiency ◽  
Collagen Scaffolds ◽  
Vascular Regeneration ◽  
Peripheral Arterial ◽  
Hepatocyte Growth Factor Mrna

Background: Chemical modification of mRNA (mmRNA) substantially improves their stability and translational efficiency within cells. Nanofibrillar collagen scaffolds were previously shown to enable the spatially localized delivery and temporally controlled release of mmRNA encoding HGF both in vitro and in vivo. Materials & methods: Herein we developed an improved slow-releasing HGF mmRNA scaffold and tested its therapeutic efficacy in a porcine model of peripheral arterial disease. Results & conclusion: The HGF mmRNA was released from scaffolds in a temporally controlled fashion in vitro with preserved transfection activity. The mmRNA scaffolds improved vascular regeneration when sutured to the ligated porcine femoral artery. These studies validate the therapeutic potential of HGF mmRNA delivery from nanofibrillar scaffolds for treatment of peripheral arterial disease.

scholarly journals A Combined Adjuvant TF–Al Consisting of TFPR1 and Aluminum Hydroxide Augments Strong Humoral and Cellular Immune Responses in Both C57BL/6 and BALB/c Mice

Vaccines ◽  
2021 ◽  
Vol 9 (12) ◽  
pp. 1408
Author(s):  
Qiao Li ◽  
Zhihua Liu ◽  
Yi Liu ◽  
Chen Liang ◽  
Jiayi Shu ◽  
...  
Keyword(s):  
Immune Responses ◽  
Vaccine Development ◽  
Inbred Mouse ◽  
Effective Vaccine ◽  
Mouse Strains ◽  
Cellular Immune Responses ◽  
Recombinant Hbsag ◽  
Cellular Immune

TFPR1 is a novel adjuvant for protein and peptide antigens, which has been demonstrated in BALB/c mice in our previous studies; however, its adjuvanticity in mice with different genetic backgrounds remains unknown, and its adjuvanticity needs to be improved to fit the requirements for various vaccines. In this study, we first compared the adjuvanticity of TFPR1 in two commonly used inbred mouse strains, BALB/c and C57BL/6 mice, in vitro and in vivo, and demonstrated that TFPR1 activated TLR2 to exert its immune activity in vivo. Next, to prove the feasibility of TFPR1 acting as a major component of combined adjuvants, we prepared a combined adjuvant, TF–Al, by formulating TFPR1 and alum at a certain ratio and compared its adjuvanticity with that of TFPR1 and alum alone using OVA and recombinant HBsAg as model antigens in both BALB/c and C57BL/6 mice. Results showed that TFPR1 acts as an effective vaccine adjuvant in both BALB/c mice and C57BL/6 mice, and further demonstrated the role of TLR2 in the adjuvanticity of TFPR1 in vivo. In addition, we obtained a novel combined adjuvant, TF–Al, based on TFPR1, which can augment antibody and cellular immune responses in mice with different genetic backgrounds, suggesting its promise for vaccine development in the future.

Abstract 17797: Noninvasive Optical Imaging of Response to On-Demand Antioxidant Therapy in a Model of Peripheral Arterial Disease

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Kristin M Poole ◽  
Christopher E Nelson ◽  
John R Martin ◽  
Devin R McCormack ◽  
Rucha V Joshi ◽  
...  
Keyword(s):  
Peripheral Arterial Disease ◽  
Hyperspectral Imaging ◽  
Time Course ◽  
Arterial Disease ◽  
Diameter Distribution ◽  
Novel Therapy ◽  
On Demand ◽  
Vessel Morphology ◽  
Peripheral Arterial

Peripheral arterial disease is often modeled by surgical induction of hind limb ischemia (HLI) in mice to study collateral vessel development. However, there is a need for methodologies that provide intravital, multifunctional, quantitative data on ischemic recovery for robust evaluation of new therapeutics. Here, we apply hyperspectral imaging and optical coherence tomography (OCT) to longitudinally assess hemoglobin oxygen saturation (SaO 2 ) and vessel morphology in response to a novel therapy. Injectable microspheres loaded with curcumin were synthesized from reactive oxygen species (ROS)-responsive poly(propylene) sulfide (PPS) to provide “on demand”, local release of the antioxidant drug curcumin to reduce tissue-damaging oxidative stress in a mouse model of diabetic HLI. Curcumin-PPS microspheres significantly reduced intracellular ROS in LPS-activated RAW 264.7 macrophages and rescued viability of 3T3 fibroblasts treated with cytotoxic levels of H 2 O 2 in vitro . HLI was induced in FVB mice with streptozotocin-induced diabetes, and curcumin-PPS or blank-PPS microspheres were injected into the ischemic limb. Curcumin-PPS significantly improved recovery of SaO 2 in the ischemic footpad relative to blank-PPS and vehicle (saline) groups over a one week time course evaluated with hyperspectral imaging (n≥8/group, p<0.05). Vessel structure in the gastrocnemius was imaged noninvasively with OCT at day 7 (Figure), revealing trends toward increased vessel area density and vessel length fraction in the curcumin-PPS group (n=5/group). The vessel diameter distribution was also extracted from OCT data. Our collective data indicate that sustained, on demand curcumin delivery has significant therapeutic promise for improving ischemic tissue recovery. Also, the hyperspectral and OCT imaging methods showcased provide quantitative, noninvasive monitoring of vasculature and can accelerate screening of novel therapies.

scholarly journals Immunosuppressive factor(s) specific for L-glutamic acid(50)-L- tyrosine(50) (GT). II. Presence of I-J determinants on the GT-suppressive factor

1977 ◽  
Vol 146 (1) ◽  
pp. 287-292 ◽  
Author(s):  
J Theze ◽  
C Waltenbaugh ◽  
ME Dorf ◽  
B Benacerraf
Keyword(s):  
T Cells ◽  
Glutamic Acid ◽  
Inbred Mouse ◽  
Inbred Mouse Strain ◽  
Antibody Responses ◽  
Mouse Strains ◽  
Suppressor T Cells ◽  
Suppressor Factor

The responses to the synthetic antigens, L-glutamic acid(60)-L- alanine(30)-L-tyrosine(10) (GAT) and L-glutamic acid(50)-L-tyrosine(50) (GT) are controlled by genes in the I region of the mouse H-2 complex (1-3). Preimmunization of the mice bearing the H-2(p,q,s) nonresponder haplotypes with GAT stimulates the development of suppressor T cells that inhibit in vivo or in vitro antibody responses to GAT complexed to the immunogenic carrier, methylated bovine serum albumin (GAT-MBSA) (4). The copolymer GT is not immunogenic in any inbred mouse strain tested, and has a suppressive effect on the antibody responses to GT-MBSA in mouse strains bearing the H-2(d,f,k,s) haplotypes; suppressor T cells have been demonstrated to be responsible for specific GT suppression (3). We have obtained specific suppressive extracts from thymus and spleen cells of GAT-or GT-primed suppressor strains (5,6). The specific suppressive T-cell factors in the active extracts have been characterized (6,7) and appear similar to the carrier-specific suppressor factor described by Tada and Taniguchi (8). These products belong to a family of newly identified molecules coded for by the I region of the H-2 complex with affinity for antigen and helper (9,10) or suppressive (5-8) regulatory activity on the immune response. Recently, Tada et al. have reported that the keyhole limpet hemocyanin (KLH)-specific suppressor factor is coded for by the I-J subregion of the H-2 complex (11). We now demonstrate also that a GT-specific suppressor factor extracted from the spleens and thymuses of B10.BR (H-2(k)) mice bears determinants controlled by the I-J subregion of the H-2 complex.

Platelet Factor 4 (PF4) And β-Thromboglobulin (BTG) In Atherosclerosis And Diabetes Mellitus

1981 ◽  
Author(s):  
F J Kazmier ◽  
E J W Bowie ◽  
W M O’Fallon ◽  
P J Palumbo
Keyword(s):  
Diabetes Mellitus ◽  
Arterial Disease ◽  
Sample Collection ◽  
Normal Range ◽  
Platelet Factor ◽  
Occlusive Arterial Disease ◽  
Objective Evidence ◽  
Peripheral Arterial

Distinguishing between in vitro and in vivo release of platelet specific proteins has led to problems in interpretation of clinical studies with PF4, and with BTG.As part of a prospective study of peripheral occlusive arterial disease in diabetes mellitus PF4 and BTG were measured together by specific radioimmunoassay in four groups of subjects age 50-70 years. Groups included (1) 106 normal subjects (NC); (2) 126 with clinical and objective evidence (transcutaneous doppler ultrasound and treadmill exercise) of peripheral arterial occlusive disease (ASO); (3) 244 with diabetes mellitus without ASO and (4) 101 with both diabetes mellitus and ASO.PF4 did not distinguish among the four groups: NC vs ASO p=. 18, NC vs DM p=.52, NC vs DM+ASO p=.73, NC vs all diabetics p=.61, and NC vs all ASO p=.46. However, BTG did distinguish the groups with vascular disease from NC: NC vs ASO p=.02, NC vs DM+ASO p<.001, NC vs DM p=.32, DM vs DM+ASO p<.01, all ASO vs all nonASO p<.001.Normal range for PF4 is 0-13 ng/ml with a median of 3.0 ng/ml, a mean of 3.0 ng/ml, and SD 1.97. Normal range for BTG is 14-46 ng/ml with a median of 26 ng/ml, a mean of 27.2 ng/ml, and SD 10.3. When PF4 and BTG are correlated (all groups included) r=.41 p<.001.PF4 and BTG levels should be performed together. When done together low PF4 levels support the absence of in vitro platelet release due to sample collection and handling. BTG levels are significantly increased in subjects with peripheral arterial disease, supporting the active role of platelets in thrombotic occlusive arterial disease.

scholarly journals Enhanced VWF biosynthesis and elevated plasma VWF due to a natural variant in the murine Vwf gene

Blood ◽  
2006 ◽  
Vol 108 (9) ◽  
pp. 3061-3067 ◽  
Author(s):  
Heidi L. Lemmerhirt ◽  
Jordan A. Shavit ◽  
Gallia G. Levy ◽  
Suzanne M. Cole ◽  
Jeffrey C. Long ◽  
...  
Keyword(s):  
Genetic Variation ◽  
Inbred Mice ◽  
Inbred Mouse ◽  
Mouse Strains ◽  
Genetic Modifiers ◽  
Wide Range ◽  
Natural Variant ◽  
Vitro Analysis

Abstract Both genetic and environmental influences contribute to the wide variation in plasma von Willebrand factor (VWF) levels observed in humans. Inbred mouse strains also have highly variable plasma VWF levels, providing a convenient model in which to study genetic modifiers of VWF. Previously, we identified a major modifier of VWF levels in the mouse (Mvwf1) as a regulatory mutation in murine Galgt2. We now report the identification of an additional murine VWF modifier (Mvwf2). Mvwf2 accounts for approximately 16% of the 8-fold plasma VWF variation (or ∼ 25% of the genetic variation) observed between the A/J and CASA/RkJ strains and maps to the murine Vwf gene itself. Twenty SNPs were identified within the coding regions of the A/J and CASA/RkJ Vwf alleles, and in vitro analysis of recombinant VWF demonstrated that a single SNP (+7970G>A) and the associated nonsynonymous amino acid change (R2657Q) confers a significant increase in VWF biosynthesis from the CASA/RkJ Vwf allele. This change appears to represent a unique gain of function that likely explains the mechanism of Mvwf2 in vivo. The identification of a natural Vwf gene variant among inbred mice affecting biosynthesis suggests that similar genetic variation may contribute to the wide range of VWF levels observed in humans.

scholarly journals Mouse hepatitis virus type 4 (JHM strains). induced fatal central nervous system disease. I. genetic control and murine neuron as the susceptible site of disease.

1981 ◽  
Vol 153 (4) ◽  
pp. 832-843 ◽  
Author(s):  
R L Knobler ◽  
M V Haspel ◽  
M B Oldstone
Keyword(s):  
Hepatitis Virus ◽  
Inbred Mouse ◽  
Neuronal Cells ◽  
Mouse Hepatitis Virus ◽  
Neuronal Cell ◽  
Autosomal Gene ◽  
Mouse Strains ◽  
Target Cells

Mouse hepatitis virus (JHM strain) type 4 induces acute encephalitis followed by death in many strains of laboratory mice. Immunohistochemical study in vivo and analysis of mouse neuronal cells in vitro both indicate that the target cells in this infection is the neuron. Further, examination of several inbred mouse strains and neuronal cells from them shows that disease expression is controlled by a single autosomal gene action at the level of the neuronal cell. Susceptibility is dominant but not H-2 linked. However, cultured neuronal cells and macrophages from SJL/J mice, which are resistant to this infection, fail to make significant amounts of infectious virus after an appropriate viral inoculation. Apparently the defect is not at the level of the virus-cell receptor, because these cells, in part, express viral antigens.

scholarly journals Induced endothelial cells from peripheral arterial disease patients and neonatal fibroblasts have comparable angiogenic properties

PLoS ONE ◽  
2021 ◽  
Vol 16 (8) ◽  
pp. e0255075
Author(s):  
Jack D. Hywood ◽  
Sara Sadeghipour ◽  
Zoe E. Clayton ◽  
Jun Yuan ◽  
Colleen Stubbs ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Peripheral Arterial Disease ◽  
Murine Model ◽  
Arterial Disease ◽  
Scid Mice ◽  
Laser Doppler ◽  
Cytokine Secretion ◽  
Endothelial Phenotype ◽  
Peripheral Arterial

Induced endothelial cells (iECs) generated from neonatal fibroblasts via transdifferentiation have been shown to have pro-angiogenic properties and are a potential therapy for peripheral arterial disease (PAD). It is unknown if iECs can be generated from fibroblasts collected from PAD patients and whether these cells are pro-angiogenic. In this study fibroblasts were collected from four PAD patients undergoing carotid endarterectomies. These cells, and neonatal fibroblasts, were transdifferentiated into iECs using modified mRNA. Endothelial phenotype and pro-angiogenic cytokine secretion were investigated. NOD-SCID mice underwent surgery to induce hindlimb ischaemia in a murine model of PAD. Mice received intramuscular injections with either control vehicle, or 1 × 106 neonatal-derived or 1 × 106 patient-derived iECs. Recovery in perfusion to the affected limb was measured using laser Doppler scanning. Perfusion recovery was enhanced in mice treated with neonatal-derived iECs and in two of the three patient-derived iEC lines investigated in vivo. Patient-derived iECs can be successfully generated from PAD patients and for specific patients display comparable pro-angiogenic properties to neonatal-derived iECs.

scholarly journals In vivo cytokine profiling in peripheral arterial disease (PAD)

2007 ◽  
Vol 21 (6) ◽  
Author(s):  
H. R . S . Girn ◽  
N.M. Orsi ◽  
S. Homer‐Vanniasinkam
Keyword(s):  
Peripheral Arterial Disease ◽  
Arterial Disease ◽  
Peripheral Arterial ◽  
Cytokine Profiling
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