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Myofibroblast ?2 adrenergic signaling amplifies cardiac hypertrophy in mice.

ABSTRACT: Abnormal ?-adrenergic signaling plays a central role in human heart failure. In mice, chronic ?-adrenergic receptor (?AR) stimulation elicits cardiac hypertrophy. It has been reported that cultured cardiac fibroblasts express ?AR; however, the functional in vivo requirement of ?AR signaling in cardiac fibroblasts during the development of cardiac hypertrophy remains elusive. ?2AR null mice exhibited attenuated hypertrophic responses to chronic ?AR stimulation upon continuous infusion of an agonist, isoprenaline (ISO), compared to those in wildtype controls, suggesting that ?2AR activation in the heart induces pro-hypertrophic effects in mice. Since ?2AR signaling is protective in cardiomyocytes, we focused on ?2AR signaling in cardiac myofibroblasts. To determine whether ?2AR signaling in myofibroblasts affects cardiac hypertrophy, we generated myofibroblast-specific transgenic mice (TG) with the catalytic subunit of protein kinase A (PKAc?) using Cre-loxP system. Myofibroblast-specific PKAc? overexpression resulted in enhanced heart weight normalized to body weight ratio, associated with an enlargement of cardiomyocytes at 12 weeks of age, indicating that myofibroblast-specific activation of PKA mediates cardiac hypertrophy in mice. Neonatal rat cardiomyocytes stimulated with conditioned media from TG cardiac fibroblasts likewise exhibited significantly more growth than those from controls. Thus, ?2AR signaling in myofibroblasts plays a substantial role in ISO-induced cardiac hypertrophy, possibly due to a paracrine effect. ?2AR signaling in cardiac myofibroblasts may represent a promising target for development of novel therapies for cardiac hypertrophy.

SUBMITTER: Imaeda A

PROVIDER: S-EPMC6704476 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature

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Myofibroblast β2 adrenergic signaling amplifies cardiac hypertrophy in mice.

Imaeda Atsuki A Tanaka Shota S Tonegawa Kota K Fuchigami Shota S Obana Masanori M Maeda Makiko M Kihara Miho M Kiyonari Hiroshi H Conway Simon J SJ Fujio Yasushi Y Nakayama Hiroyuki H

Biochemical and biophysical research communications 20190123 1

Abnormal β-adrenergic signaling plays a central role in human heart failure. In mice, chronic β-adrenergic receptor (βAR) stimulation elicits cardiac hypertrophy. It has been reported that cultured cardiac fibroblasts express βAR; however, the functional in vivo requirement of βAR signaling in cardiac fibroblasts during the development of cardiac hypertrophy remains elusive. β2AR null mice exhibited attenuated hypertrophic responses to chronic βAR stimulation upon continuous infusion of an agoni ...[more]

PMID: 30683314

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Project description:Cardiac hypertrophy is a context-dependent phenomenon wherein a myriad of biochemical and biomechanical factors regulate myocardial growth through a complex large-scale signaling network. Although numerous studies have investigated hypertrophic signaling pathways, less is known about hypertrophy signaling as a whole network and how this network acts in a context-dependent manner. Here, we developed a systematic approach, CLASSED (Context-specific Logic-bASed Signaling nEtwork Development), to revise a large-scale signaling model based on context-specific data and identify main reactions and new crosstalks regulating context-specific response. CLASSED involves four sequential stages with an automated validation module as a core which builds a logic-based ODE model from the interaction graph and outputs the model validation percent. The context-specific model is developed by estimation of default parameters, classified qualitative validation, hybrid Morris-Sobol global sensitivity analysis, and discovery of missing context-dependent crosstalks. Applying this pipeline to our prior-knowledge hypertrophy network with context-specific data revealed key signaling reactions which distinctly regulate cell response to isoproterenol, phenylephrine, angiotensin II and stretch. Furthermore, with CLASSED we developed a context-specific model of β-adrenergic cardiac hypertrophy. The model predicted new crosstalks between calcium/calmodulin-dependent pathways and upstream signaling of Ras in the ISO-specific context. Experiments in cardiomyocytes validated the model's predictions on the role of CaMKII-Gβγ and CaN-Gβγ interactions in mediating hypertrophic signals in ISO-specific context and revealed a difference in the phosphorylation magnitude and translocation of ERK1/2 between cardiac myocytes and fibroblasts. CLASSED is a systematic approach for developing context-specific large-scale signaling networks, yielding insights into new-found crosstalks in β-adrenergic cardiac hypertrophy.

Dataset Information

Myofibroblast ?2 adrenergic signaling amplifies cardiac hypertrophy in mice.

Publications

Myofibroblast β2 adrenergic signaling amplifies cardiac hypertrophy in mice.

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