4 results on '"Clifford, Brian T."'
Search Results
2. Overexpression of Nitric Oxide Synthase Restores Circulating Angiogenic Cell Function in Patients With Coronary Artery Disease: Implications for Autologous Cell Therapy for Myocardial Infarction.
- Author
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Chen Q, Varga M, Wang X, Haddad DJ, An S, Medzikovic L, Derakhshandeh R, Kostyushev DS, Zhang Y, Clifford BT, Luu E, Danforth OM, Rafikov R, Gong W, Black SM, Suchkov SV, Fineman JR, Heiss C, Aschbacher K, Yeghiazarians Y, and Springer ML
- Subjects
- Adult, Aged, Animals, Case-Control Studies, Cell Movement, Cells, Cultured, Coculture Techniques, Coronary Artery Disease diagnosis, Disease Models, Animal, Female, Humans, Male, Mice, SCID, Middle Aged, Myocardial Infarction enzymology, Myocardial Infarction genetics, Myocardial Infarction pathology, Myocardial Infarction physiopathology, Nitric Oxide Synthase Type III genetics, Phenotype, RNA Interference, Recovery of Function, Regeneration, Signal Transduction, Time Factors, Transduction, Genetic, Transfection, Coronary Artery Disease enzymology, Endothelial Progenitor Cells enzymology, Endothelial Progenitor Cells transplantation, Myocardial Infarction surgery, Neovascularization, Physiologic, Nitric Oxide metabolism, Nitric Oxide Synthase Type III metabolism, Stem Cell Transplantation methods
- Abstract
Background: Circulating angiogenic cells (CACs) are peripheral blood cells whose functional capacity inversely correlates with cardiovascular risk and that have therapeutic benefits in animal models of cardiovascular disease. However, donor age and disease state influence the efficacy of autologous cell therapy. We sought to determine whether age or coronary artery disease (CAD) impairs the therapeutic potential of CACs for myocardial infarction (MI) and whether the use of ex vivo gene therapy to overexpress endothelial nitric oxide (NO) synthase (eNOS) overcomes these defects., Methods and Results: We recruited 40 volunteers varying by sex, age (< or ≥45 years), and CAD and subjected their CACs to well-established functional tests. Age and CAD were associated with reduced CAC intrinsic migration (but not specific response to vascular endothelial growth factor, adherence of CACs to endothelial tubes, eNOS mRNA and protein levels, and NO production. To determine how CAC function influences therapeutic potential, we injected the 2 most functional and the 2 least functional CAC isolates into mouse hearts post MI. The high-function isolates substantially improved cardiac function, whereas the low-function isolates led to cardiac function only slightly better than vehicle control. Transduction of the worst isolate with eNOS cDNA adenovirus increased NO production, migration, and cardiac function of post-MI mice implanted with the CACs. Transduction of the best isolate with eNOS small interfering RNA adenovirus reduced all of these capabilities., Conclusions: Age and CAD impair multiple functions of CACs and limit therapeutic potential for the treatment of MI. eNOS gene therapy in CACs from older donors or those with CAD has the potential to improve autologous cell therapy outcomes., (© 2016 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.)
- Published
- 2016
- Full Text
- View/download PDF
3. Pleiotrophin gene therapy for peripheral ischemia: evaluation of full-length and truncated gene variants.
- Author
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Fang Q, Mok PY, Thomas AE, Haddad DJ, Saini SA, Clifford BT, Kapasi NK, Danforth OM, Usui M, Ye W, Luu E, Sharma R, Bartel MJ, Pathmanabhan JA, Ang AA, Sievers RE, Lee RJ, and Springer ML
- Subjects
- Animals, Carrier Proteins metabolism, Cell Movement, Cell Transformation, Neoplastic metabolism, Cells, Cultured, Coronary Vessels pathology, Cytokines metabolism, Endoplasmic Reticulum metabolism, Endoplasmic Reticulum Stress, Hindlimb blood supply, Hindlimb pathology, Human Umbilical Vein Endothelial Cells physiology, Humans, Male, Mice, Mice, Nude, Mice, SCID, Muscle, Skeletal pathology, Myoblasts metabolism, Myoblasts transplantation, Myocardium pathology, Myocytes, Smooth Muscle physiology, Neovascularization, Physiologic, Peptide Fragments metabolism, Carrier Proteins genetics, Cytokines genetics, Genetic Therapy, Ischemia therapy, Muscle, Skeletal blood supply, Peptide Fragments genetics
- Abstract
Pleiotrophin (PTN) is a growth factor with both pro-angiogenic and limited pro-tumorigenic activity. We evaluated the potential for PTN to be used for safe angiogenic gene therapy using the full length gene and a truncated gene variant lacking the domain implicated in tumorigenesis. Mouse myoblasts were transduced to express full length or truncated PTN (PTN or T-PTN), along with a LacZ reporter gene, and injected into mouse limb muscle and myocardium. In cultured myoblasts, PTN was expressed and secreted via the Golgi apparatus, but T-PTN was not properly secreted. Nonetheless, no evidence of uncontrolled growth was observed in cells expressing either form of PTN. PTN gene delivery to myocardium, and non-ischemic skeletal muscle, did not result in a detectable change in vascularity or function. In ischemic hindlimb at 14 days post-implantation, intramuscular injection with PTN-expressing myoblasts led to a significant increase in skin perfusion and muscle arteriole density. We conclude that (1) delivery of the full length PTN gene to muscle can be accomplished without tumorigenesis, (2) the truncated PTN gene may be difficult to use in a gene therapy context due to inefficient secretion, (3) PTN gene delivery leads to functional benefit in the mouse acute ischemic hindlimb model.
- Published
- 2013
- Full Text
- View/download PDF
4. Donor myocardial infarction impairs the therapeutic potential of bone marrow cells by an interleukin-1-mediated inflammatory response.
- Author
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Wang X, Takagawa J, Lam VC, Haddad DJ, Tobler DL, Mok PY, Zhang Y, Clifford BT, Pinnamaneni K, Saini SA, Su R, Bartel MJ, Sievers RE, Carbone L, Kogan S, Yeghiazarians Y, Hermiston M, and Springer ML
- Subjects
- Animals, Echocardiography, Flow Cytometry, Male, Mice, Mice, Inbred C57BL, Myocardial Infarction pathology, Bone Marrow Transplantation methods, Interleukin-1 metabolism, Myocardial Infarction immunology, Myocardial Infarction therapy, Tissue Donors
- Abstract
Delivery of bone marrow cells (BMCs) to the heart has substantially improved cardiac function in most rodent models of myocardial infarction (MI), but clinical trials of BMC therapy have led to only modest improvements. Rodent models typically involve intramyocardial injection of BMCs from distinct donor individuals who are healthy. In contrast, autologous BMCs from individuals after MI are used for clinical trials. Using BMCs from donor mice after MI, we discovered that recent MI impaired BMC therapeutic efficacy. MI led to myocardial inflammation and an increased inflammatory state in the bone marrow, changing the BMC composition and reducing their efficacy. Injection of a general anti-inflammatory drug or a specific interleukin-1 inhibitor to donor mice after MI prevented this impairment. Our findings offer an explanation of why human trials have not matched the success of rodent experiments and suggest potential strategies to improve the success of clinical autologous BMC therapy.
- Published
- 2011
- Full Text
- View/download PDF
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