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Dive into the research topics where Jeffrey A. Poynter is active.

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Featured researches published by Jeffrey A. Poynter.


Surgery | 2010

Signaling via GPR30 protects the myocardium from ischemia/ reperfusion injury

Brent R. Weil; Mariuxi C. Manukyan; Jeremy L. Herrmann; Yue Wang; Aaron M. Abarbanell; Jeffrey A. Poynter; Daniel R. Meldrum

BACKGROUND Estrogen may protect against the development of cardiovascular disease. Recently, a receptor known as GPR30 that seems to mediate estrogens nongenomic effects has been identified. We hypothesized that the activation of GPR30 protects cardiac function and decreases myocardial inflammation after global ischemia/reperfusion (I/R). METHODS Hearts from male Sprague-Dawley rats were perfused via Langendorff and treated with either (1) vehicle; (2) 10 nm of the GPR30 agonist, G-1; or (3) 100 nm of G-1; they then were subjected to 25 minutes of ischemia and 40 minutes of reperfusion. Cardiac functional parameters were measured continuously. Ventricular tissue was analyzed for tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta, and IL-6. RESULTS At end-reperfusion, the left ventricular developed pressure in the 100-nm G-1 group was improved compared with vehicle (26% +/- 12% equilibrium vs 54% +/- 9% equilibrium; P < .05). Similar findings were noted when comparing the 100-nm G-1 group with the vehicle in terms of +dP/dt (53% +/- 12% equilibrium vs 26% +/- 19%, respectively; P < .05) and -dP/dt (56% +/- 15% equilibrium vs 22% +/- 16% equilibrium, respectively; P < .05). TNF-alpha, IL-1beta, and IL-6 levels were lower in myocardium of the 100-nm G-1 group compared with the vehicle (P < .05). CONCLUSION The GPR30 agonist, G-1, improves functional recovery and decreases myocardial inflammation after global I/R. GPR30 may play an important role in estrogens ability to protect the heart against I/R injury.


Surgery | 2010

Mesenchymal stem cells attenuate myocardial functional depression and reduce systemic and myocardial inflammation during endotoxemia.

Brent R. Weil; Mariuxi C. Manukyan; Jeremy L. Herrmann; Yue Wang; Aaron M. Abarbanell; Jeffrey A. Poynter; Daniel R. Meldrum

BACKGROUND Endotoxemia is associated with depressed cardiac function during sepsis. Mesenchymal stem cells (MSCs) possess an ability to modulate the inflammatory response during sepsis, but it is unknown whether MSCs possess the ability to reduce endotoxemia-induced myocardial injury and dysfunction. METHODS Endotoxemia was induced in rats via injection of lipopolysaccharide (LPS). Animals were divided into the following groups: (1) saline + saline; (2) LPS + saline; (3) LPS + MSCs; and (4) LPS + LLC-PK1 renal epithelial cells (differentiated control). At 6 hours, animals were anesthetized, serum was collected, and hearts were extracted and perfused via the isolated heart system. Hearts and serum were analyzed for tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta, IL-6, and IL-10. RESULTS The administration of LPS depressed myocardial function. Treatment with MSCs ameliorated this depression. Serum TNF-alpha, IL-1beta, and IL-6 were elevated in LPS-treated groups. Treatment with MSCs was associated with reduced levels of these cytokines. A trend toward reduced myocardial TNF-alpha and significant reductions in myocardial IL-1beta and IL-6 were observed in the MSC-treated group. IL-10 levels were increased after the LPS administration in both serum and myocardium. Serum levels were increased further after treatment with MSCs. CONCLUSION Treatment with MSCs during endotoxemia reduces systemic and myocardial inflammation and is associated with a reduction in LPS-induced myocardial functional depression.


PLOS ONE | 2011

Sca-1+ cardiac stem cells mediate acute cardioprotection via paracrine factor SDF-1 following myocardial ischemia/reperfusion

Chunyan Huang; Hongmei Gu; Qing Yu; Mariuxi C. Manukyan; Jeffrey A. Poynter; Meijing Wang

Background Cardiac stem cells (CSCs) promote myocardial recovery following ischemia through their regenerative properties. However, little is known regarding the implication of paracrine action by CSCs in the setting of myocardial ischemia/reperfusion (I/R) injury although it is well documented that non-cardiac stem cells mediate cardioprotection via the production of paracrine protective factors. Here, we studied whether CSCs could initiate acute protection following global myocardial I/R via paracrine effect and what component from CSCs is critical to this protection. Methodology/Principal Findings A murine model of global myocardial I/R was utilized to investigate paracrine effect of Sca-1+ CSCs on cardiac function. Intracoronary delivery of CSCs or CSC conditioned medium (CSC CM) prior to ischemia significantly improved myocardial function following I/R. siRNA targeting of VEGF in CSCs did not affect CSC-preserved myocardial function in response to I/R injury. However, differentiation of CSCs to cardiomyocytes (DCSCs) abolished this protection. Through direct comparison of the protein expression profiles of CSCs and DCSCs, SDF-1 was identified as one of the dominant paracrine factors secreted by CSCs. Blockade of the SDF-1 receptor by AMD3100 or downregulated SDF-1 expression in CSCs by specific SDF-1 siRNA dramatically impaired CSC-induced improvement in cardiac function and increased myocardial damage following I/R. Of note, CSC treatment increased myocardial STAT3 activation after I/R, whereas downregulation of SDF-1 action by blockade of the SDF-1 receptor or SDF-1 siRNA transfection abolished CSC-induced STAT3 activation. In addition, inhibition of STAT3 activation attenuated CSC-mediated cardioprotection following I/R. Finally, post-ischemic infusion of CSC CM was shown to significantly protect I/R-caused myocardial dysfunction. Conclusions/Significance This study suggests that CSCs acutely improve post-ischemic myocardial function through paracrine factor SDF-1 and up-regulated myocardial STAT3 activation.


Journal of Surgical Research | 2012

Advances in mesenchymal stem cell research in sepsis.

Todd J. Wannemuehler; Mariuxi C. Manukyan; Benjamin D. Brewster; Joshua Rouch; Jeffrey A. Poynter; Yue Wang; Daniel R. Meldrum

BACKGROUND Sepsis remains a source of morbidity and mortality in the postoperative patient despite appropriate resuscitative and antimicrobial approaches. Recent research has focused upon additional interventions such as exogenous cell-based therapy. Mesenchymal stem cells (MSCs) exhibit multiple beneficial properties through their capacity for homing, attenuating the inflammatory response, modulating immune cells, and promoting tissue healing. Recent animal trials have provided evidence that MSCs may be useful therapeutic adjuncts. MATERIALS AND METHODS A directed search of recent medical literature was performed utilizing PubMed to examine the pathophysiology of sepsis, mechanisms of mesenchymal stem cell interaction with host cells, sepsis animal models, and recent trials utilizing stem cells in sepsis. RESULTS MSCs continue to show promise in the treatment of sepsis by their intrinsic ability to home to injured tissue, secrete paracrine signals to limit systemic and local inflammation, decrease apoptosis in threatened tissues, stimulate neoangiogenesis, activate resident stem cells, beneficially modulate immune cells, and exhibit direct antimicrobial activity. These effects are associated with reduced organ dysfunction and improved survival in animal models. CONCLUSION Research utilizing animal models of sepsis has provided a greater understanding of the beneficial properties of MSCs. Their capacity to home to sites of injury and use paracrine mechanisms to change the local environment to ultimately improve organ function and survival make MSCs attractive in the treatment of sepsis. Future studies are needed to further evaluate the complex interactions between MSCs and host tissues.


PLOS ONE | 2010

TLR4 Inhibits Mesenchymal Stem Cell (MSC) STAT3 Activation and Thereby Exerts Deleterious Effects on MSC–Mediated Cardioprotection

Yue Wang; Aaron M. Abarbanell; Jeremy L. Herrmann; Brent R. Weil; Mariuxi C. Manukyan; Jeffrey A. Poynter; Daniel R. Meldrum

Background Bone marrow-derived mesenchymal stem cells (MSC) improve myocardial recovery after ischemia/reperfusion (I/R) injury. These effects are mediated in part by the paracrine secretion of angiogenic and tissue growth-promoting factors. Toll-like receptor 4 (TLR4) is expressed by MSC and induces apoptosis and inhibits proliferation in neuronal progenitors as well as many other cell types. It is unknown whether knock-out (KO) of TLR4 will change the paracrine properties of MSC and in turn improve MSC-associated myocardial protection. Methodology/Principal Findings This study explored the effect of MSC TLR4 on the secretion of angiogenic factors and chemokines in vitro by using ELISA and cytokine array assays and investigated the role of TLR4 on MSC-mediated myocardial recovery after I/R injury in an isolated rat heart model. We observed that MSC isolated from TLR4 KO mice exhibited a greater degree of cardioprotection in a rat model of myocardial I/R injury. This enhanced protection was associated with increased angiogenic factor production, proliferation and differentiation. TLR4-dificiency was also associated with decreased phosphorylation of PI-3K and AKT, but increased activation of STAT3. siRNA targeting of STAT3 resulted in attenuation of the enhanced cardioprotection of TLR4-deficient MSC. Conclusions/Significance This study indicates that TLR4 exerts deleterious effects on MSC-derived cardioprotection following I/R by a STAT3 inhibitory mechanism.


Shock | 2011

Intravenous infusion of mesenchymal stem cells is associated with improved myocardial function during endotoxemia.

Brent R. Weil; Jeremy L. Herrmann; Aaron M. Abarbanell; Mariuxi C. Manukyan; Jeffrey A. Poynter; Daniel R. Meldrum

Mesenchymal stem cells (MSCs) possess immunomodulatory properties and may curtail the inflammatory response that characterizes sepsis and other systemic inflammatory states. We aimed to determine whether intravenous infusion of MSCs is associated with reduced inflammation and improved myocardial function in a rat model of endotoxemia. Adult Sprague-Dawley rats were administered saline (vehicle) or LPS (5 mg/kg) via tail vein injection. Treatments, either vehicle or 2 × 106 MSCs, were infused 1 h later via tail vein. Animals were randomly assigned to the following groups: (a) vehicle + vehicle (control; n = 6), (b) LPS + vehicle (n = 6), or (c) LPS + MSCs (n = 6). Six hours after induction of endotoxemia, left ventricular ejection fraction (EF) and fractional shortening (FS) was assessed via parasternal short-axis M-mode echocardiography. Hearts and serum were collected for determination of cytokine levels via enzyme-linked immunosorbent assay. Animals injected with LPS + vehicle exhibited depressed cardiac function as indicated by a 26% and 37% reduction in EF and FS from baseline, respectively. Treatment with MSCs was associated with improved cardiac function compared with vehicle treatment as indicated by a reduction in EF and FS of only 10% and 17%, respectively (P < 0.05). Myocardial levels of TNF-&agr;, IL-1&bgr;, and IL-6 were elevated in LPS-treated animals versus control. Similarly, serum levels of IL-1&bgr;, IL-6, and IL-10 were increased in LPS-treated animals. Treatment with MSCs, however, was associated with significant reductions in serum levels of IL-1&bgr; and IL-6 and in myocardial levels of TNF-&agr;, IL-1&bgr;, and IL-6. In addition, treatment with MSCs was associated with a further increase in serum IL-10. Infusion of MSCs modulates the systemic inflammatory response and is associated with improved cardiac function during endotoxemia.


American Journal of Physiology-heart and Circulatory Physiology | 2010

Toll-like receptor 2 mediates mesenchymal stem cell-associated myocardial recovery and VEGF production following acute ischemia-reperfusion injury.

Aaron M. Abarbanell; Yue Wang; Jeremy L. Herrmann; Brent R. Weil; Jeffrey A. Poynter; Mariuxi C. Manukyan; Daniel R. Meldrum

Toll-like receptor 2 (TLR2), a key component of the innate immune system, is linked to inflammation and myocardial dysfunction after ischemia-reperfusion injury (I/R). Treatment of the heart with mesenchymal stem cells (MSCs) is known to improve myocardial recovery after I/R in part by paracrine factors such as VEGF. However, it is unknown whether TLR2 activation on the MSCs affects MSC-mediated myocardial recovery and VEGF production. We hypothesized that the knockout of TLR2 on the MSCs (TLR2KO MSCs) would 1) improve MSC-mediated myocardial recovery and 2) increase myocardial and MSC VEGF release. With the isolated heart perfusion system, Sprague-Dawley rat hearts were subjected to I/R and received one of three intracoronary treatments: vehicle, male wild-type MSCs (MWT MSCs), or TL2KO MSCs. All treatments were performed immediately before ischemia, and heart function was measured continuously. Postreperfusion, heart homogenates were analyzed for myocardial VEGF production. Contrary to our hypothesis, only MWT MSC treatment significantly improved the recovery of left ventricular developed pressure and the maximal positive and negative values of the first derivative of pressure. In addition, VEGF production was greatest in hearts treated with MWT MSCs. To investigate MSC production of VEGF, MSCs were activated with TNF in vitro and the supernatants collected for ELISA. In vitro basal levels of MSC VEGF production were similar. However, with TNF activation, MWT MSCs produced significantly more VEGF, whereas activated TLR2KO MSC production of VEGF was unchanged. Finally, we observed that MWT MSCs proliferated more rapidly than TLR2KO MSCs. These data indicate that TLR2 may be essential to MSC-mediated myocardial recovery and VEGF production.


World Journal for Pediatric and Congenital Heart Surgery | 2014

Repair of anomalous aortic origin of a coronary artery in 113 patients: a Congenital Heart Surgeons' Society report.

Jeffrey A. Poynter; Igor Bondarenko; Erle H. Austin; William M. Decampli; Jeffrey P. Jacobs; Gerhard Ziemer; Paul M. Kirshbom; Christo I. Tchervenkov; Tara Karamlou; Eugene H. Blackstone; Henry L. Walters; J. William Gaynor; Carlos M. Mery; Jeffrey M. Pearl; Christopher A. Caldarone; William G. Williams; Marshall L. Jacobs; Constantine Mavroudis

Background: Anomalous aortic origin of a coronary artery (AAOCA) encompasses a wide morphologic spectrum, which has impeded consensus regarding indications for the diverse repair strategies. We constructed a profile of current surgical techniques and explore their application to morphologic variants. Methods: Patients <30 years old (n = 113) with isolated AAOCA who underwent operations at 29 Congenital Heart Surgeons Society (CHSS) institutions from 1998 to 2012 were identified from the CHSS AAOCA Registry. Operative findings were related to surgical techniques at index repairs by cross-tabulation. Results: Anomalous origin of the left main or left anterior descending coronary artery was present in 33 (29%) patients and of the right coronary artery in 78 (69%) patients; 2 arteries originated directly above the commissure between the left and right sinuses. There were 101 (89%) interarterial and intramural (IA/IM) arteries, 10 (9%) were interarterial but not intramural (IA/NIM) and 2 (2%) were neither interarterial nor intramural. Intramural arteries were unroofed in 100 (88%) operations, usually with intimal tacking after incision (n = 47) or excision (n = 25) of the common wall. Coronary reimplantation (n = 11), pulmonary artery relocation (n = 7; 5 for IA/NIM), simple ostioplasty (without unroofing; n = 3), coronary artery bypass grafting (n = 2), and ostial window (n = 1) were less common. In 37 (33%) operations, a valvar commissure was taken down; 33 were resuspended. Conclusion: Current surgical repair of AAOCA is individualized to morphology, particularly the presence of intramural and/or interarterial segments. This report is foundational for future planned CHSS studies that will examine interventional and noninterventional outcomes and ultimately guide management of AAOCA.


Surgery | 2011

Interleukin-10 protects the ischemic heart from reperfusion injury via the STAT3 pathway

Mariuxi C. Manukyan; Collin H. Alvernaz; Jeffrey A. Poynter; Yue Wang; Benjamin D. Brewster; Brent R. Weil; Aaron M. Abarbanell; Jeremy L. Herrmann; Brandon J. Crowe; A.C. Keck; Daniel R. Meldrum

BACKGROUND Cardiac surgery induces the release of inflammatory mediators that can prolong cardiac dysfunction after operative intervention. Interleukin-10 (IL-10), a potent inhibitor of myocardial inflammation, is a known factor in myocardial protection after ischemia/reperfusion (I/R) injury. We hypothesized that IL-10 activity during initial reperfusion is mediated through the signal transducer and activator of transcription 3 (STAT3) pathway. METHODS Adult rat hearts were isolated and perfused via Langendorff protocol and subjected to global I/R. After determining the effective IL-10 dose, hearts were administered vehicle, IL-10, or IL-10 + Stattic (specific STAT3 inhibitor) 1 min prior to ischemia. After reperfusion, hearts were sectioned and assessed for levels of myocardial inflammatory cytokines and protein. RESULTS The IL-10 minimum effective dose was 1 μg. IL-10-treated hearts had improved markedly myocardial function after global I/R compared to both vehicle and IL-10 + Stattic groups. In addition, IL-10 treatment was associated with a significant decrease in myocardial interleukin-1β (IL-1β) and interleukin-6 (IL-6) and increase in myocardial IL-10. Myocardial STAT3 was elevated markedly in IL-10 treated hearts. CONCLUSION IL-10 improves myocardial function after acute global I/R and suppresses inflammation through the STAT3 pathway. The administration of anti-inflammatory agents may have potential therapeutic applications in cardiac surgery.


Surgery | 2012

Pretreating mesenchymal stem cells with interleukin-1β and transforming growth factor-β synergistically increases vascular endothelial growth factor production and improves mesenchymal stem cell-mediated myocardial protection after acute ischemia.

Yong Luo; Yue Wang; Jeffrey A. Poynter; Mariuxi C. Manukyan; Jeremy L. Herrmann; Aaron M. Abarbanell; Brent R. Weil; Daniel R. Meldrum

BACKGROUND Mesenchymal stem cells (MSCs) improve postischemic myocardial function in part through their secretion of growth factors such as vascular endothelial growth factor (VEGF). Pretreating MSCs with various cytokines or small molecules can improve VEGF secretion and MSC-mediated cardioprotection. However, whether 1 cytokine can potentiate the effect of another cytokine in MSC pretreatment to achieve a synergistic effect on VEGF production and cardioprotection is poorly studied. METHODS MSCs were treated with interleukin (IL)-1β and/or transforming growth factor (TGF)-β1 for 24 hours before experiments. VEGF production was determined by enzyme-linked immunosorbent assay. Isolated hearts from adult male Sprague-Dawley rats were subjected to 15 minutes of equilibration, 25 minutes of ischemia, and 40 minutes reperfusion. Hearts (n = 5-7 per group) were randomly infused with vehicle, untreated MSCs, or MSCs pretreated with IL-1β and/or TGF-β1. Specific inhibitors were used to delineate the roles of p38 mitogen-activated protein kinase (MAPK) and SMAD3 in IL-1β- and TGF-β1-mediated stimulation of MSCs. RESULTS MSCs cotreated with IL-1β and TGF-β1 exhibited synergistically increased VEGF secretion, and they greatly improved postischemic myocardial functional recovery. Ablation of p38 MAPK and SMAD3 activation with specific inhibitors negated both IL-1β- and TGF-β1-mediated VEGF production in MSCs and the ability of these pretreated MSCs to improve myocardial recovery after ischemia. CONCLUSION Pretreating MSCs with 2 cytokines may be useful to fully realize the potential of cell-based therapies for ischemic tissues.

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Yue Wang

University of Arizona

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