Properties of G-protein modulated receptor-adenylyl cyclase system in myocardium of spontaneously hypertensive rats treated with adriamycin

Fu, Michael; Matoba, Munetoshi; Liang, Qi-Ming; Sjögren, Klas-Göran; Hjalmarson, Åke

doi:10.1016/0167-5273(94)90061-2

Cited by 23 publications

(8 citation statements)

References 22 publications

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“…Alternatively, one can speculate that compensatory factors such as adenylyl cyclase downregulation, decreased G s activity or increased G i activity following b 2 -AR stimulation may lead to cAMP levels and PDE4 activity and expression remaining unchanged at this point in the development of ADR cardiotoxicity at 3 weeks post-ADR. 16,39,40 Further experiments need to be performed to elucidate intracellular processes involved. In the current study, the diminished response to DMI administration correlates with decreased [ 3 H]CGP12177 retention, as reduced surface b-AR presence potentially translates to decreased cAMP production.…”

Section: Discussionmentioning

confidence: 99%

Alterations of pre- and postsynaptic noradrenergic signaling in a rat model of adriamycin-induced cardiotoxicity

Kenk

Thackeray

Thorn

et al. 2010

Journal of Nuclear Cardiology

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Section: Discussionmentioning

confidence: 99%

Alterations of pre- and postsynaptic noradrenergic signaling in a rat model of adriamycin-induced cardiotoxicity

Kenk

Thackeray

Thorn

et al. 2010

Journal of Nuclear Cardiology

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“…There is evidence that β-AR signaling alterations are present in doxorubicin cardiomyopathy as they are in other forms of dilated cardiomyopathy. Animal models show increased circulating norepinephrine, downregulation of β-ARs, downregulation of Gs and upregulation of Gi [42,43]. β-Blockers have been shown to improve cardiac function in both rats and humans with established doxorubicin cardiomyopathy [44,45].…”

Section: Discussionmentioning

confidence: 99%

Differential cardiotoxic/cardioprotective effects of β-adrenergic receptor subtypes in myocytes and fibroblasts in doxorubicin cardiomyopathy

Fajardo

Zhao

Powers

et al. 2006

Journal of Molecular and Cellular Cardiology

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beta-Adrenoceptor (beta-AR) subtypes act through different signaling pathways to regulate cardiac function and remodeling. Previous in vivo data show a markedly enhanced cardiotoxic response to doxorubicin in beta2-/- mice, which is rescued by the additional deletion of the beta1-AR. We determined whether this differential response was myocyte specific by examining the effects of doxorubicin in myocytes and fibroblasts from WT and beta1, beta2 and beta1/beta2-/- mice. Cells were exposed to doxorubicin at 1-50 microM and viability and apoptosis assessed at 6, 24 and 48 h. WT myocytes showed a time and dose-dependent decrease in viability (42% decrease at 1 microM after 24 h). beta2-/- Myocytes showed a greater decrease in viability vs. WT (20.8% less at 6 h; 14% less at 24 h, P<0.05); beta1-/- and beta1/beta2-/- myocytes showed enhanced survival (beta1-/- 11%; beta1/beta2-/- 18% greater than WT, P<0.05). TUNEL staining demonstrated a similar differential susceptibility (WT 26% apoptotic nuclei, beta2-/- 45.9%, beta1/beta2-/- 16.8%, P<0.05). beta2-/- Fibroblasts also showed enhanced toxicity. Pertussis toxin pretreatment of WT cells decreased survival similar to the beta2-/-, suggesting a role for Gi signaling. JNK was differentially activated in beta2-/- myocytes after doxorubicin and its inhibition increased cardiotoxicity. In conclusion, the differential cardioprotective/cardiotoxic effects mediated by beta1 vs. beta2-AR subtypes in knockout mice are recapitulated in myocytes isolated from these mice. beta2-ARs appear to play a cardioprotective role, whereas beta1-ARs a cardiotoxic role.

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“…Myocyte cell death by both apoptosis and necrosis has also been implicated, and the net loss of cells may further contribute to ‘cardiac wasting’. Finally, anthracyclines induce changes in adrenergic function and adenylate cyclase[14, 15], as well as abnormalities in Ca 2+ handling[16], all critical for the dynamic regulation of cardiac function. The extent to which each of these contributes to the dose-dependent clinical heart failure in anthracycline treated patient remains controversial.…”

Section: Overview Of Anthracycline Cardiotoxicitymentioning

confidence: 99%

Mechanisms of Anthracycline Cardiac Injury: Can We Identify Strategies for Cardioprotection?

Sawyer

Peng

Chen

et al. 2010

Progress in Cardiovascular Diseases

235

162

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SummaryAnthracycline antibiotics have saved the lives of many cancer victims in the 50 plus years since their discovery. A major limitation of their use is the dose-limiting cardiotoxicity. Efforts focusing on understanding the biochemical basis for anthracycline cardiac effects have provided several strategies currently in clinical use: limit dose exposure; encapsulate anthracyclines in liposomes to reduce myocardial uptake; administer concurrently with the iron chelator dexrazoxane to reduce free ironcatalyzed reactive oxygen species formation; modification of anthracycline structure in an effort to reduce myocardial toxicity. In spite of these efforts, anthracycline-induced heart failure continues to occur with consequences for both morbidity and mortality. Our inability to predict and prevent anthracycline cardiotoxicity is in part due to the fact that the molecular and cellular mechanisms remain controversial and incompletely understood. Studies examining the effects of anthracyclines in cardiac myocytes in vitro and small animals in vivo have demonstrated several forms of cardiac injury, and it remains unclear how these translate to the clinical setting. Given the clinical evidence that myocyte death occurs after anthracycline exposure in the form of elevations in serum troponin, myocyte cell death appears to be a probable mechanism for anthracycline-induced cardiac injury. Other mechanisms of myocyte injury include the development of cellular 'sarcopenia' characterized by disruption of normal sarcomere structure. Anthracyclines suppress expression of several cardiac transcription factors, and this may play a role in the development of myocyte death as well as sarcopenia. Degradation of the giant myofilament protein titin may represent an important proximal step that leads to accelerated myofilament degradation. An interesting interaction has been noted clinically between anthracyclines and newer cancer therapies that target the erbB2 receptor tyrosine kinase. There is now evidence that erbB2 signaling in response to the ligand neuregulin regulates anthracycline uptake into cells via the multidrug-resistance protein. Therefore upregulation of cardiac neuregulin signaling may be one strategy to limit myocardial anthracycline injury. Moreover, assessing an individual's risk for anthracycline injury may be improved by having some measure of endogenous activity of this and other myocardial protective signals. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. 1]): 1) inhibition of both DNA replication and RNA transcription; 2) free radical generation, leading to DNA damag...

show abstract

Properties of G-protein modulated receptor-adenylyl cyclase system in myocardium of spontaneously hypertensive rats treated with adriamycin

Cited by 23 publications

References 22 publications

Alterations of pre- and postsynaptic noradrenergic signaling in a rat model of adriamycin-induced cardiotoxicity

Alterations of pre- and postsynaptic noradrenergic signaling in a rat model of adriamycin-induced cardiotoxicity

Differential cardiotoxic/cardioprotective effects of β-adrenergic receptor subtypes in myocytes and fibroblasts in doxorubicin cardiomyopathy

Mechanisms of Anthracycline Cardiac Injury: Can We Identify Strategies for Cardioprotection?

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