β -Adrenergic Cardiac Hypertrophy is Mediated Primarily by the β1-Subtype in the Rat Heart

Morisco, Carmine; Zebrowski, David C.; Vatner, Dorothy E.; Vatner, Stephen F.; Sadoshima, Junichi

doi:10.1006/jmcc.2000.1332

Cited by 141 publications

(117 citation statements)

References 50 publications

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“…At the age of 8 weeks, we observed AP-1 and CRE activation associated with IL-6 expression, whereas NF-κB was activated in the LV at 22 weeks. Parallel with the enhanced IL-6 expression, we observe augmented ventricular proANP expression (Figure 3), consistent with a β-adrenoceptor-mediated contribution to ventricular proANP-induction (15). Similar to the mouse model, failing human myocardium shows an increase in IL-6 mRNA and protein expression as well as increased CRE and AP-1 activity together with additional activation of NF-κB.…”

Section: β-Adrenergic Activation Of Ap-1 and Cresupporting

confidence: 73%

Activation of AP-1 Contributes to the β-Adrenoceptor-Mediated Myocardial Induction of Interleukin-6

Rohrbach

Engelhardt

Werdan

et al. 2007

Mol Med

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The induction of proinflammatory cytokines in stressed myocardium is considered an innate immune response, but the role of β-adrenergic signaling in this proinflammatory response and the mechanisms of cardioprotection by β-blockers are not fully understood. In the present study, we analyzed interleukin-6 (IL-6) formation and promoter activation in β-adrenoceptor-stimulated neonatal rat cardiomyocytes, in transgenic mice with cardiac overexpression of β1-adrenoceptors, and in failing human myocardium. IL-6 formation and release in cultured cardiomyocytes under β-adrenoceptor stimulation requires the activation of activating protein-1 (AP-1) binding sites and of cAMP response elements (CRE) in the IL-6 promoter, but this release (140 ± 6 pg/mL medium under 10 -6 M isoproterenol vs. 81 ± 3 pg/mL unstimulated, P < 0.05) is moderate compared with that under inflammatory stimulation (855 ± 44 pg/mL, endotoxin 0.1µg/mL). Similarly, IL-6 is induced together with CRE-and AP-1 activation in the left ventricle (LV) of β1-transgenic mice before the onset of failure. However, we observed IL-6 induction with activation of NF-κB in addition to CRE and AP-1 in β1-transgenic mice at the age of 22 weeks and in explanted human LV after full development of failure. Treatment with β-blockers lowered myocardial IL-6 as well as AP-1, NF-κB, and CRE activation. Therefore, the activation of AP-1 and CRE is part of β-adrenergic signal transduction for IL-6 induction in nonfailing and failing cardiomyocytes, whereas NF-κB activation contributes only in overloaded failing myocardium.

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Section: β-Adrenergic Activation Of Ap-1 and Cresupporting

confidence: 73%

Activation of AP-1 Contributes to the β-Adrenoceptor-Mediated Myocardial Induction of Interleukin-6

Rohrbach

Engelhardt

Werdan

et al. 2007

Mol Med

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“…Abnormalities in β-adrenergic receptor signal transduction are not involved only in cardiac functional impairment, they also play a role in cardiac structural changes observed in heart failure being involved in the transition from compensated cardiac hypertrophy to decompensated heart failure (Morisco et al 2001, Lowes et al 2002. The exposure to high levels of circulating cathecholamines has been reported to be toxic to cardiac myocytes (Rona 1985, Mann et al 1992), leading to myofibrillar degradation and increased cardiac collagen volume fraction mediated by β-adrenergic receptor stimulation.…”

Section: The Cardiac β-Adrenergic Pathway In Heart Failurementioning

confidence: 99%

Neurohumoral activation in heart failure: the role of adrenergic receptors

Brum

Rolim

Bacurau

et al. 2006

An. Acad. Bras. Ciênc.

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Heart failure (HF) is a common endpoint for many forms of cardiovascular disease and a significant cause of morbidity and mortality. The development of end-stage HF often involves an initial insult to the myocardium that reduces cardiac output and leads to a compensatory increase in sympathetic nervous system activity. Acutely, the sympathetic hyperactivity through the activation of beta-adrenergic receptors increases heart rate and cardiac contractility, which compensate for decreased cardiac output. However, chronic exposure of the heart to elevated levels of catecholamines released from sympathetic nerve terminals and the adrenal gland may lead to further pathologic changes in the heart, resulting in continued elevation of sympathetic tone and a progressive deterioration in cardiac function. On a molecular level, altered beta-adrenergic receptor signaling plays a pivotal role in the genesis and progression of HF. beta-adrenergic receptor number and function are decreased, and downstream mechanisms are altered. In this review we will present an overview of the normal beta-adrenergic receptor pathway in the heart and the consequences of sustained adrenergic activation in HF. The myopathic potential of individual components of the adrenergic signaling will be discussed through the results of research performed in genetic modified animals. Finally, we will discuss the potential clinical impact of beta-adrenergic receptor gene polymorphisms for better understanding the progression of HF.

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“…In addition, IL-18 was shown to induce ANF gene transcription (20). Because re-expression of the fetal gene ANF is mostly associated with myocardial hypertrophy and failure (21,22), we hypothesized that IL-18 might act as a pro-hypertrophic cytokine. Therefore, we investigated the direct effects of IL-18 on cardiomyocyte hypertrophy, and we explored the signal transduction pathways activated by IL-18 in inducing cardiomyocyte hypertrophy using the murine atrial cardiomyocyte cell line HL-1 (23).…”

mentioning

confidence: 99%

Interleukin-18 Is a Pro-hypertrophic Cytokine That Acts through a Phosphatidylinositol 3-Kinase-Phosphoinositide-dependent Kinase-1-Akt-GATA4 Signaling Pathway in Cardiomyocytes

Chandrasekar

Mummidi

Claycomb

et al. 2005

Journal of Biological Chemistry

119

113

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In patients with congestive heart failure, high serum levels of the proinflammatory cytokine interleukin (IL)-18 were reported. A positive correlation was described between serum IL-18 levels and the disease severity. IL-18 has also been shown to induce atrial natriuretic factor (ANF) gene expression in adult cardiomyocytes. Because re-expression of the fetal gene ANF is mostly associated with hypertrophy, a hallmark of heart failure, we hypothesized that IL-18 induces cardiomyocyte hypertrophy. Treatment of the cardiomyocyte cell line HL-1 with IL-18 induced hypertrophy as characterized by increases in protein synthesis, phosphorylated p70 S6 kinase, and ribosomal S6 protein levels as well as cell surface area. Furthermore, IL-18 induced ANF gene transcription in a time-dependent manner as evidenced by increased ANF secretion and ANF promoter-driven reporter gene activity. Investigation into possible signal transduction pathways mediating IL-18 effects revealed that IL-18 activates phosphoinositide 3-kinase (PI3K), an effect that was blocked by wortmannin and LY-294002. IL-18 induced Akt phosphorylation and stimulated its activity, effects that were abolished by Akt inhibitor or knockdown. IL-18 stimulated GATA4 DNA binding activity and increased transcription of a reporter gene driven by multimerized GATA4-binding DNA elements. Pharmacological inhibition or knockdown studies revealed that IL-18 induced cardiomyocyte hypertrophy and ANF gene transcription via PI3K, PDK1, Akt, and GATA4. Most importantly, IL-18 induced ANF gene transcription and hypertrophy of neonatal rat ventricular myocytes via PI3K-, Akt-, and GATA4-dependent signaling. Together these data provide the first evidence that IL-18 induces cardiomyocyte hypertrophy via PI3K-dependent signaling, defines a mechanism of IL-18-mediated ANF gene transcription, and further supports a role for IL-18 in inflammatory heart diseases including heart failure.

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β -Adrenergic Cardiac Hypertrophy is Mediated Primarily by the β1-Subtype in the Rat Heart

Cited by 141 publications

References 50 publications

Activation of AP-1 Contributes to the β-Adrenoceptor-Mediated Myocardial Induction of Interleukin-6

Activation of AP-1 Contributes to the β-Adrenoceptor-Mediated Myocardial Induction of Interleukin-6

Neurohumoral activation in heart failure: the role of adrenergic receptors

Interleukin-18 Is a Pro-hypertrophic Cytokine That Acts through a Phosphatidylinositol 3-Kinase-Phosphoinositide-dependent Kinase-1-Akt-GATA4 Signaling Pathway in Cardiomyocytes

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