Cardioplegia and Angiotensin II Receptor Antagonists Modulate Signal Transducers and Activators of Transcription Activation in Neonatal Rat Myocytes

Lucchese, Gianluca; Cambi, Giulia Elisa; Rita, Fabrizio De; Faggian, Giuseppe; Mazzucco, Alessandro; Modesti, Pietro Amedeo; Luciani, Giovanni Battista

doi:10.1111/j.1525-1594.2011.01386.x

Cited by 7 publications

(11 citation statements)

References 30 publications

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“…Once STAT proteins are activated by phosphorylation, they dimerize to translocate into the nucleus [22,23], where they bind to the DNA, triggering the expression of pro- and anti-inflammatory molecules that might aggravate or reduce the damage produced in the brain. Within the family of the STATs, STAT3 is described as an anti-inflammatory protein in adults although its activation mechanism in neonates remains unclear [24]. STAT3 is activated by some interleukins such as interleukin (IL)-6, IL-11, IL-10, IL-20 and IL-22 [25,26].…”

Section: Introductionmentioning

confidence: 99%

Temporal Expression of Cytokines and Signal Transducer and Activator of Transcription Factor 3 Activation after Neonatal Hypoxia/Ischemia in Mice

Shrivastava¹,

Llovera²,

Recasens³

et al. 2013

Dev Neurosci

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Hypoxia/ischemia (HI) is a prevalent reason for neonatal brain injury with inflammation being an inevitable phenomenon following such injury; but there is a scarcity of data regarding the signaling pathway involved and the effector molecules. The signal transducer and activator of transcription factor 3 (STAT3) is known to modulate injury following imbalance between pro- and anti-inflammatory cytokines in peripheral and central nervous system injury making it a potential molecule for study. The current study investigates the temporal expression of interleukin (IL)-6, IL-1β, tumor necrosis factor-α, IL-1ra, IL-4, IL-10, IL-13 and phosphorylated STAT3 (pSTAT3) after carotid occlusion and hypoxia (8% O₂, 55 min) in postnatal day 7 C57BL/6 mice from 3 h to 21 days after hypoxia. Protein array illustrated notable changes in cytokines expressed in both hemispheres in a time-dependent manner. The major pro-inflammatory cytokines showing immediate changes between ipsi- and contralateral hemispheres were IL-6 and IL-1β. The anti-inflammatory cytokines IL-4 and IL-13 demonstrated a delayed augmentation with no prominent differences between hemispheres, while IL-1ra showed two distinct peaks of expression spread over time. We also illustrate for the first time the spatiotemporal activation of pSTAT3 (Y705 phosphorylation) after a neonatal HI in mice brain. The main regions expressing pSTAT3 were the hippocampus and the corpus callosum. pSTAT3+ cells were mostly a subpopulation of activated astrocytes (GFAP+) and microglia/macrophages (F4/80+) seen only in the ipsilateral hemisphere at most time points studied (till 7 days after hypoxia). The highest expression of pSTAT3+ cells was observed to be around 24-48 h, where the presence of pSTAT3+ astrocytes and pSTAT3+ microglia/macrophages was seen by confocal micrographs. In conclusion, our study highlights a synchronized expression of some pro- and anti-inflammatory cytokines, especially in the long term not previously defined. It also points towards a significant role of STAT3 signaling following micro- and astrogliosis in the pathophysiology of neonatal HI-related brain injury. In the study, a shift from pro-inflammatory to anti-inflammatory cytokine profile was also noted as the injury progressed. We suggest that while designing efficient neuroprotective therapies using inflammatory molecules, the time of intervention and balance between the pro- and anti-inflammatory cytokines must be considered.

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Section: Introductionmentioning

confidence: 99%

Temporal Expression of Cytokines and Signal Transducer and Activator of Transcription Factor 3 Activation after Neonatal Hypoxia/Ischemia in Mice

Shrivastava¹,

Llovera²,

Recasens³

et al. 2013

Dev Neurosci

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“…46 Addition of an AT 1 R antagonist (valsartan) to cardioplegia reduces activation of the proinflammatory STAT2 and STAT5 pathways and decreases expression of interleukin-1β in myocytes from neonatal rats. 47,48 Importantly, these effects are not seen with an AT 2 R antagonist. 47 These observations suggest that inhibition of the angiotensin II pathway is a potentially useful strategy to limit ischaemic damage in cardioplegia, although whether this works in intact hearts from young and old animals of both sexes is as yet unclear.…”

Section: Other Pharmacological Strategiesmentioning

confidence: 99%

“…Some have used drugs that block angiotensin II type 1 receptors (AT 1 R), because angiotensin II is known to activate “signal transducer and activator of transcription” (STAT) pathways that are implicated in detrimental effects of myocardial ischaemia . Addition of an AT 1 R antagonist (valsartan) to cardioplegia reduces activation of the pro‐inflammatory STAT2 and STAT5 pathways and decreases expression of interleukin‐1β in myocytes from neonatal rats . Importantly, these effects are not seen with an AT 2 R antagonist .…”

Section: Pharmacologic Agents In Cardioplegia In Pre‐clinical Models mentioning

confidence: 99%

Novel cardioprotection strategies for the aged heart: evidence from pre‐clinical studies

Kane

Howlett

2016

Clin Exp Pharma Physio

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The incidence of cardiovascular disease is rising as the population ages. This has led to an increase in the need to perform cardiac surgery in older patients. However, aged hearts are particularly susceptible to reperfusion injury following periods of myocardial ischaemia that occur during cardiac surgery. Indeed, older adults experience myocardial dysfunction and reduced survival post-surgery compared to younger people and certain groups, including older women and frail older adults, are at particular risk. This highlights the need to design cardioprotective strategies specifically for the ageing heart. Cardioprotection during surgery is often accomplished by perfusing the heart with chemical arresting agents, known as cardioplegic solutions. New protective strategies have been developed and tested in animal models, where cardioplegic solutions have been modified by changing their temperature, chemical components and/or the frequency of delivery. In addition, drugs designed to activate cardioprotective mechanisms or to inhibit mechanisms involved in injury have been added to improve the efficacy of these solutions. However, most experimental studies have developed and optimized cardioplegic solutions in hearts from younger male animals. This review discusses pre-clinical models used to optimize cardioplegic solutions, with an emphasis on the few studies that have used hearts from older animals. Pharmacologic agents that have been shown to enhance the benefits of cardioplegia in younger hearts and could, in theory, protect vulnerable older hearts are also considered. We emphasize the need to conduct studies in frail older animals of both sexes to facilitate translation of laboratory-based observations to the clinic.

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“…Gianluca Lucchese et al. (76) of the University of Verona, Verona, Italy investigated the effects that signal transducers and activators of the transcription (STATs) signaling pathway play on the modulation of apoptosis after ischemia and reperfusion. The effects of angiotension II type 1 (AT1) and angiotension II type 2 (AT2) receptor antagonist added to cardioplegia on the downstream response of different STATs connected with proinflammatory pathways (STAT2, STAT5), and prohypertrophic and antiapoptotic pathways (STAT3) were studied.…”

Section: Cardiopulmonary Support and Membrane Oxygenationmentioning

confidence: 99%

Artificial Organs 2011: A Year in Review

Malchesky¹

2012

Artificial Organs

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In this Editor's Review, articles published in 2011 are organized by category and briefly summarized. As the official journal of The International Federation for Artificial Organs, The International Faculty for Artificial Organs, and the International Society for Rotary Blood Pumps, Artificial Organs continues in the original mission of its founders "to foster communications in the field of artificial organs on an international level."Artificial Organs continues to publish developments and clinical applications of artificial organ technologies in this broad and expanding field of organ replacement, recovery, and regeneration from all over the world. We take this time also to express our gratitude to our authors for offering their work to this journal. We offer our very special thanks to our reviewers who give so generously of time and expertise to review, critique, and especially provide meaningful suggestions to the author's work whether eventually accepted or rejected. Without these excellent and dedicated reviewers, the quality expected from such a journal would not be possible. We also express our special thanks to our Publisher, Wiley-Blackwell, for their expert attention and support in the production and marketing of Artificial Organs. In this Editor's Review, that historically has been widely well-received by our readership, we aim to provide a brief reflection of the currently available worldwide knowledge that is intended to advance and better human life while providing insight for continued application of technologies and methods of organ replacement, recovery, and regeneration. We look forward to recording further advances in the coming years.

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Cardioplegia and Angiotensin II Receptor Antagonists Modulate Signal Transducers and Activators of Transcription Activation in Neonatal Rat Myocytes

Cited by 7 publications

References 30 publications

Temporal Expression of Cytokines and Signal Transducer and Activator of Transcription Factor 3 Activation after Neonatal Hypoxia/Ischemia in Mice

Temporal Expression of Cytokines and Signal Transducer and Activator of Transcription Factor 3 Activation after Neonatal Hypoxia/Ischemia in Mice

Novel cardioprotection strategies for the aged heart: evidence from pre‐clinical studies

Artificial Organs 2011: A Year in Review

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