Senescent Impairment in Synergistic Cytokine Pathways That Provide Rapid Cardioprotection in the Rat Heart

Xaymardan, Munira; Zheng, Jingang; Duignan, Inga; Chin, Andrew I.; Holm, Jacquelyne M.; Ballard, Victoria L. T.; Edelberg, Jay M.

doi:10.1084/jem.20031639

Cited by 42 publications

(36 citation statements)

References 45 publications

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“…To this end, we have previously demonstrated that the delayed kinetics of PDGF-AB-mediated cardioprotection can be eliminated by the codelivery of PDGF-AB and the growth factors downstream from PDGF-AB in cardiac angiogenic pathways at the time of acute coronary occlusion to act synergistically to reduce cardiac cell death and decrease myocardial injury (27). Indeed, the significant increase in TUNEL staining after PDGF-AB injection in the old IPC rats is consistent with the diminished survival of this treatment group after permanent LAD occlusion compared with the rats receiving IPC alone.…”

Section: Discussionmentioning

confidence: 99%

“…Importantly, codelivery of platelet-derived growth factor (PDGF)-AB can reverse these impairments and restores cardioprotection to the aging heart. Mechanistically, the actions of PDGF-AB are mediated in combination with its induction of both vascular endothelial growth factor (VEGF) and angiopoietin (Ang)-2 (but not VEGF and Ang-2 without PDGF-AB) to acutely suppress apoptosis and reduce myocardial infarction (27). From these findings, we hypothesized that strategies targeting PDGF-AB-based pathways (PDGF-AB alone or in combination with VEGF and Ang-2) would improve functional outcomes under conditions associated with dysregulation of TNF-␣-mediated cardioprotection in the aging heart.…”

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confidence: 99%

“…The above procedure was also performed in young and old rats without LAD occlusion as controls. Additional groups of old rats received intramyocardial injections of PDGF-AB alone or a combination termed PVA of PDGF-AB, VEGF, and Ang-2 [each factor at a dose of 100 ng as previously employed (27) in a total volume of 50 l: two injections, 25 l on either side of the LAD, using a 30-gauge needle syringe] that were given after the first ischemic episode. The sample size was Ն3 rats per test condition.…”

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Growth factor-mediated reversal of senescent dysfunction of ischemia-induced cardioprotection

Zheng¹,

Chin²,

Duignan³

et al. 2006

American Journal of Physiology-Heart and Circulatory Physiology

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. Growth factor-mediated reversal of senescent dysfunction of ischemia-induced cardioprotection. Am J Physiol Heart Circ Physiol 290: H525-H530, 2006. First published September 23, 2005 doi:10.1152/ajpheart.00470.2005.-Based on the role of tumor necrosis factor-␣ (TNF-␣) in ischemic preconditioning (IPC) and the age-associated loss of both TNF-␣-induced platelet-derived growth factor-AB (PDGF-AB)-mediated cardioprotection and IPC-mediated cardioprotection, we hypothesized that targeting of PDGF-AB-based pathways would restore cardioprotection by IPC in the aging heart. To study this, IPC was induced in 4-and 24-mo-old F344 rats. Sections of young hearts isolated 1 day post-IPC revealed increased TNF-␣ compared with controls. In old rats, TNF-␣ was higher at baseline than IPC young rats and was not significantly altered after IPC. Treatment of old rats with PDGF-AB with vascular endothelial growth factor and angiopoietin-2 (a combination termed PVA), but not PDGF-AB alone, at the time of IPC decreased TNF-␣. In addition, when compared with young hearts, IPC induced greater apoptosis in the old hearts, which was decreased with PVA treatment but was markedly increased with PDGF-AB. To test the significance of these findings, additional rats underwent permanent coronary ligation 1 day post-IPC. IPC was cardioprotective in young rats [14 days postmyocardial infarction (MI), fractional shortening 29 Ϯ 6% vs. control MI 17 Ϯ 4%, P Ͻ 0.05; Masson's trichrome stain MI size: 13 Ϯ 2% vs. control MI 17 Ϯ 4% left ventricular area (LVA); P Ͻ 0.05]. In old rats, however, IPC reduced the post-MI 14-day survival (33% vs. controls 67%; P Ͻ 0.05). Treatment of IPC-aging rats with PVA, but not PDGF-AB-alone, reversed IPC-induced mortality (PVA-IPC-MI survival, 88%; PDGF-AB-IPC-MI, 14%) and reduced myocardial injury (fractional shortening: PVA-IPC, 31 Ϯ 1% vs. control MI, 21 Ϯ 6%, P Ͻ 0.05; MI size: PVA-IPC, 12 Ϯ 2% vs. control MI, 18 Ϯ 3% LVA, P Ͻ 0.05) and thus demonstrated that PDGF-AB-based pathways can reverse the senescent impairment in IPC-mediated cardioprotection.aging; myocardial infarction; preconditioning AGE-RELATED ALTERATIONS in tumor necrosis factor-␣ (TNF-␣) pathways may contribute to the increased risk of cardiac disease and more severe cardiovascular pathophysiology in the geriatric population. Specifically, the recent results from the ABC Health Study revealed that in persons over 65 yr of age, TNF-␣ is more predictive of future cardiovascular events compared with C-reactive protein (CRP) (5). Moreover, clinical studies of inflammatory markers have linked elevations in TNF-␣ with an increased incidence of congestive heart failure after myocardial infarction (25). These findings in conjunction with the age-related increases in TNF-␣ in the systemic circulation (3) as well as the coronary arteries (7) suggest that strategies targeted at the actions of TNF

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Section: Discussionmentioning

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Growth factor-mediated reversal of senescent dysfunction of ischemia-induced cardioprotection

Zheng¹,

Chin²,

Duignan³

et al. 2006

American Journal of Physiology-Heart and Circulatory Physiology

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“…Thus, the injurious potential of inflammatory mediators in patients with myocardial infarction may have been overstated due to extrapolation from young animals to human patients. In addition, senescent ischemic hearts show impairment of important cardioprotective pathways involving TNF-α [339] and PDGF-AB [340] and have a decreased anti-apoptotic response to administration of GranulocyteColony Stimulating Factor (G-CSF) and SCF [341] in comparison with young animals.…”

Section: Do Anti-inflammatory Approaches Reduce Cardiomyocyte Injury?mentioning

confidence: 99%

The immune system and cardiac repair

Frangogiannis

2008

Pharmacological Research

568

499

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Myocardial infarction is the most common cause of cardiac injury and results in acute loss of a large number of myocardial cells. Because the heart has negligible regenerative capacity, cardiomyocyte death triggers a reparative response that ultimately results in formation of a scar and is associated with dilative remodeling of the ventricle. Cardiac injury activates innate immune mechanisms initiating an inflammatory reaction. Toll Like Receptor-mediated pathways, the complement cascade and reactive oxygen generation induce Nuclear Factor (NF)-κB activation and upregulate chemokine and cytokine synthesis in the infarcted heart. Chemokines stimulate the chemotactic recruitment of inflammatory leukocytes into the infarct, while cytokines promote adhesive interactions between leukocytes and endothelial cells, resulting in transmigration of inflammatory cells into the site of injury. Monocyte subsets play distinct roles in phagocytosis of dead cardiomyocytes and in granulation tissue formation through the release of growth factors. Clearance of dead cells and matrix debris may be essential for resolution of inflammation and transition into the reparative phase. Transforming Growth Factor (TGF)-β plays a crucial role in cardiac repair by suppressing inflammation while promoting myofibroblast phenotypic modulation and extracellular matrix deposition. Myofibroblast proliferation and angiogenesis result in formation of highly vascularized granulation tissue. As the healing infarct matures, fibroblasts become apoptotic and a collagen-based matrix is formed, while many infarct neovessels acquire a muscular coat and uncoated vessels regress. Timely resolution of the inflammatory infiltrate and spatial containment of the inflammatory and reparative response into the infarcted area are essential for optimal infarct healing. Targeting inflammatory pathways following infarction may reduce cardiomyocyte injury and attenuate adverse remodeling. In addition, understanding the role of the immune system in cardiac repair is necessary in order to design optimal strategies for cardiac regeneration.

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“…Specifically, we hypothesized that studies in the pinnal allograft model would identify the vascular/endothelial compartment(s) that underlie the diabetic impairment in cardiac vascular function. Indeed, because this model has facilitated the advancement of novel cardioprotective approaches (7,29), the results of pinnal allograft studies in diabetic mice could direct the development of molecular-and/or cellularbased approaches that may reduce diabetic-related cardiovascular diseases.…”

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Synergistic targeting with bone marrow-derived cells and PDGF improves diabetic vascular function

Klibansky¹,

Chin²,

Duignan³

et al. 2006

American Journal of Physiology-Heart and Circulatory Physiology

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Senescent Impairment in Synergistic Cytokine Pathways That Provide Rapid Cardioprotection in the Rat Heart

Cited by 42 publications

References 45 publications

Growth factor-mediated reversal of senescent dysfunction of ischemia-induced cardioprotection

Growth factor-mediated reversal of senescent dysfunction of ischemia-induced cardioprotection

The immune system and cardiac repair

Synergistic targeting with bone marrow-derived cells and PDGF improves diabetic vascular function

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