8 results on '"Haddad, Daniel J."'
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, Qiumei, Varga, Monika, Wang, Xiaoyin, Haddad, Daniel J, An, Songtao, Medzikovic, Lejla, Derakhshandeh, Ronak, Kostyushev, Dmitry S, Zhang, Yan, Clifford, Brian T, Luu, Emmy, Danforth, Olivia M, Rafikov, Ruslan, Gong, Wenhui, Black, Stephen M, Suchkov, Sergey V, Fineman, Jeffrey R, Heiss, Christian, Aschbacher, Kirstin, Yeghiazarians, Yerem, and Springer, Matthew L
- Published
- 2016
3. 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, Qiumei, Varga, Monika, Wang, Xiaoyin, Haddad, Daniel J, An, Songtao, Medzikovic, Lejla, Derakhshandeh, Ronak, Kostyushev, Dmitry S, Zhang, Yan, Clifford, Brian T, Luu, Emmy, Danforth, Olivia M, Rafikov, Ruslan, Gong, Wenhui, Black, Stephen M, Suchkov, Sergey V, Fineman, Jeffrey R, Heiss, Christian, Aschbacher, Kirstin, Yeghiazarians, Yerem, and Springer, Matthew L
- Subjects
Cells ,Cultured ,Animals ,Humans ,Mice ,SCID ,Myocardial Infarction ,Disease Models ,Animal ,Nitric Oxide ,Stem Cell Transplantation ,Coculture Techniques ,Case-Control Studies ,Transduction ,Genetic ,Transfection ,Recovery of Function ,Regeneration ,Signal Transduction ,Cell Movement ,RNA Interference ,Neovascularization ,Physiologic ,Phenotype ,Time Factors ,Adult ,Aged ,Middle Aged ,Female ,Male ,Nitric Oxide Synthase Type III ,Coronary Artery Disease ,Endothelial Progenitor Cells ,circulating angiogenic cells ,endothelial progenitor cells ,gene therapy ,myocardial infarction ,nitric oxide synthase ,Cells ,Cultured ,Mice ,SCID ,Disease Models ,Animal ,Transduction ,Genetic ,Neovascularization ,Physiologic ,Prevention ,Cardiovascular ,Heart Disease - Coronary Heart Disease ,Biotechnology ,Atherosclerosis ,Clinical Research ,Heart Disease ,Cardiorespiratory Medicine and Haematology - 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.
- Published
- 2016
4. Pleiotrophin gene therapy for peripheral ischemia: evaluation of full-length and truncated gene variants.
- Author
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Fang, Qizhi, Mok, Pamela Y, Thomas, Anila E, Haddad, Daniel J, Saini, Shereen A, Clifford, Brian T, Kapasi, Neel K, Danforth, Olivia M, Usui, Minako, Ye, Weisheng, Luu, Emmy, Sharma, Rikki, Bartel, Maya J, Pathmanabhan, Jeremy A, Ang, Andrew AS, Sievers, Richard E, Lee, Randall J, and Springer, Matthew L
- Subjects
Pleiotrophin ,Myoblasts ,Angiogenesis ,Endothelial cells ,Hindlimb ischemia - 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
5. Pleiotrophin Gene Therapy for Peripheral Ischemia: Evaluation of Full-Length and Truncated Gene Variants
- Author
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Fang, Qizhi, Mok, Pamela Y, Thomas, Anila E, Haddad, Daniel J, Saini, Shereen A, Clifford, Brian T, Kapasi, Neel K, Danforth, Olivia M, Usui, Minako, Ye, Weisheng, Luu, Emmy, Sharma, Rikki, Bartel, Maya J, Pathmanabhan, Jeremy A, Ang, Andrew A. S, Sievers, Richard E, Lee, Randall J, Springer, Matthew L, and Hsieh, Patrick CH.
- Published
- 2013
6. Pharmacological inhibition of S-nitrosoglutathione reductase improves endothelial vasodilatory function in rats in vivo
- Author
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Chen, Qiumei, Sievers, Richard E, Varga, Monika, Kharait, Sourabh, Haddad, Daniel J, Patton, Aaron K, Delany, Christopher S, Mutka, Sarah C, Blonder, Joan P, Dubé, Gregory P, Rosenthal, Gary J, and Springer, Matthew L
- Subjects
Heart Disease ,Hypertension ,Cardiovascular ,Administration ,Oral ,Aldehyde Oxidoreductases ,Animals ,Antihypertensive Agents ,Blood Pressure ,Cells ,Cultured ,Disease Models ,Animal ,Dose-Response Relationship ,Drug ,Endothelium ,Vascular ,Enzyme Inhibitors ,Femoral Artery ,Humans ,Injections ,Intravenous ,Kidney ,Mice ,Nitric Oxide ,Nitric Oxide Synthase Type III ,Rats ,Rats ,Inbred Dahl ,Rats ,Sprague-Dawley ,Sodium Chloride ,Dietary ,Time Factors ,Vasodilation ,Vasodilator Agents ,hypertension ,flow-mediated vasodilation ,nitric oxide ,S-nitrosoglutathione ,S-nitrosoglutathione reductase ,Biological Sciences ,Medical and Health Sciences ,Physiology - Abstract
Nitric oxide (NO) exerts a wide range of cellular effects in the cardiovascular system. NO is short lived, but S-nitrosoglutathione (GSNO) functions as a stable intracellular bioavailable NO pool. Accordingly, increased levels can facilitate NO-mediated processes, and conversely, catabolism of GSNO by the regulatory enzyme GSNO reductase (GSNOR) can impair these processes. Because dysregulated GSNOR can interfere with processes relevant to cardiovascular health, it follows that inhibition of GSNOR may be beneficial. However, the effect of GSNOR inhibition on vascular activity is unknown. To study the effects of GSNOR inhibition on endothelial function, we treated rats with a small-molecule inhibitor of GSNOR (N6338) that has vasodilatory effects on isolated aortic rings and assessed effects on arterial flow-mediated dilation (FMD), an NO-dependent process. GSNOR inhibition with a single intravenous dose of N6338 preserved FMD (15.3 ± 5.4 vs. 14.2 ± 6.3%, P = nonsignificant) under partial NO synthase inhibition that normally reduces FMD by roughly 50% (14.1 ± 2.9 vs. 7.6 ± 4.4%, P < 0.05). In hypertensive rats, daily oral administration of N6338 for 14 days reduced blood pressure (170.0 ± 5.3/122.7 ± 6.4 vs. 203.8 ± 1.9/143.7 ± 7.5 mmHg for vehicle, P < 0.001) and vascular resistance index (1.5 ± 0.4 vs. 3.2 ± 1.0 mmHg · min · l(-1) for vehicle, P < 0.001), and restored FMD from an initially impaired state (7.4 ± 1.7%, day 0) to a level (13.0 ± 3.1%, day 14, P < 0.001) similar to that observed in normotensive rats. N6338 also reversed the pathological kidney changes exhibited by the hypertensive rats. GSNOR inhibition preserves FMD under conditions of impaired NO production and protects against both microvascular and conduit artery dysfunction in a model of hypertension.
- Published
- 2013
7. Pharmacological inhibition of S-nitrosoglutathione reductase improves endothelial vasodilatory function in rats in vivo
- Author
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Chen, Qiumei, Sievers, Richard E, Varga, Monika, Kharait, Sourabh, Haddad, Daniel J, Patton, Aaron K, Delany, Christopher S, Mutka, Sarah C, Blonder, Joan P, Dubé, Gregory P, Rosenthal, Gary J, and Springer, Matthew L
- Abstract
Nitric oxide (NO) exerts a wide range of cellular effects in the cardiovascular system. NO is short lived, but S-nitrosoglutathione (GSNO) functions as a stable intracellular bioavailable NO pool. Accordingly, increased levels can facilitate NO-mediated processes, and conversely, catabolism of GSNO by the regulatory enzyme GSNO reductase (GSNOR) can impair these processes. Because dysregulated GSNOR can interfere with processes relevant to cardiovascular health, it follows that inhibition of GSNOR may be beneficial. However, the effect of GSNOR inhibition on vascular activity is unknown. To study the effects of GSNOR inhibition on endothelial function, we treated rats with a small-molecule inhibitor of GSNOR (N6338) that has vasodilatory effects on isolated aortic rings and assessed effects on arterial flow-mediated dilation (FMD), an NO-dependent process. GSNOR inhibition with a single intravenous dose of N6338 preserved FMD (15.3 ± 5.4 vs. 14.2 ± 6.3%, P = nonsignificant) under partial NO synthase inhibition that normally reduces FMD by roughly 50% (14.1 ± 2.9 vs. 7.6 ± 4.4%, P < 0.05). In hypertensive rats, daily oral administration of N6338 for 14 days reduced blood pressure (170.0 ± 5.3/122.7 ± 6.4 vs. 203.8 ± 1.9/143.7 ± 7.5 mmHg for vehicle, P < 0.001) and vascular resistance index (1.5 ± 0.4 vs. 3.2 ± 1.0 mmHg · min · l(-1) for vehicle, P < 0.001), and restored FMD from an initially impaired state (7.4 ± 1.7%, day 0) to a level (13.0 ± 3.1%, day 14, P < 0.001) similar to that observed in normotensive rats. N6338 also reversed the pathological kidney changes exhibited by the hypertensive rats. GSNOR inhibition preserves FMD under conditions of impaired NO production and protects against both microvascular and conduit artery dysfunction in a model of hypertension.
- Published
- 2013
8. Pharmacological inhibition of S-nitrosoglutathione reductase improves endothelial vasodilatory function in rats in vivo.
- Author
-
Chen, Qiumei, Sievers, Richard E, Varga, Monika, Kharait, Sourabh, Haddad, Daniel J, Patton, Aaron K, Delany, Christopher S, Mutka, Sarah C, Blonder, Joan P, Dubé, Gregory P, Rosenthal, Gary J, and Springer, Matthew L
- Subjects
Kidney ,Femoral Artery ,Endothelium ,Vascular ,Cells ,Cultured ,Animals ,Rats ,Inbred Dahl ,Humans ,Mice ,Rats ,Rats ,Sprague-Dawley ,Hypertension ,Disease Models ,Animal ,Nitric Oxide ,Sodium Chloride ,Dietary ,Aldehyde Oxidoreductases ,Antihypertensive Agents ,Vasodilator Agents ,Enzyme Inhibitors ,Administration ,Oral ,Injections ,Intravenous ,Blood Pressure ,Vasodilation ,Dose-Response Relationship ,Drug ,Time Factors ,Nitric Oxide Synthase Type III ,hypertension ,flow-mediated vasodilation ,nitric oxide ,S-nitrosoglutathione ,S-nitrosoglutathione reductase ,Cardiovascular ,Heart Disease ,Endothelium ,Vascular ,Cells ,Cultured ,Inbred Dahl ,Sprague-Dawley ,Disease Models ,Animal ,Sodium Chloride ,Dietary ,Administration ,Oral ,Injections ,Intravenous ,Dose-Response Relationship ,Drug ,Physiology ,Biological Sciences ,Medical and Health Sciences - Abstract
Nitric oxide (NO) exerts a wide range of cellular effects in the cardiovascular system. NO is short lived, but S-nitrosoglutathione (GSNO) functions as a stable intracellular bioavailable NO pool. Accordingly, increased levels can facilitate NO-mediated processes, and conversely, catabolism of GSNO by the regulatory enzyme GSNO reductase (GSNOR) can impair these processes. Because dysregulated GSNOR can interfere with processes relevant to cardiovascular health, it follows that inhibition of GSNOR may be beneficial. However, the effect of GSNOR inhibition on vascular activity is unknown. To study the effects of GSNOR inhibition on endothelial function, we treated rats with a small-molecule inhibitor of GSNOR (N6338) that has vasodilatory effects on isolated aortic rings and assessed effects on arterial flow-mediated dilation (FMD), an NO-dependent process. GSNOR inhibition with a single intravenous dose of N6338 preserved FMD (15.3 ± 5.4 vs. 14.2 ± 6.3%, P = nonsignificant) under partial NO synthase inhibition that normally reduces FMD by roughly 50% (14.1 ± 2.9 vs. 7.6 ± 4.4%, P < 0.05). In hypertensive rats, daily oral administration of N6338 for 14 days reduced blood pressure (170.0 ± 5.3/122.7 ± 6.4 vs. 203.8 ± 1.9/143.7 ± 7.5 mmHg for vehicle, P < 0.001) and vascular resistance index (1.5 ± 0.4 vs. 3.2 ± 1.0 mmHg · min · l(-1) for vehicle, P < 0.001), and restored FMD from an initially impaired state (7.4 ± 1.7%, day 0) to a level (13.0 ± 3.1%, day 14, P < 0.001) similar to that observed in normotensive rats. N6338 also reversed the pathological kidney changes exhibited by the hypertensive rats. GSNOR inhibition preserves FMD under conditions of impaired NO production and protects against both microvascular and conduit artery dysfunction in a model of hypertension.
- Published
- 2013
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