Sustained β-AR stimulation induces synthesis and secretion of growth factors in cardiac myocytes that affect on cardiac fibroblast activation

Nuamnaichati, Narawat; Sato, Vilasinee Hirunpanich; Moongkarndi, Primchanien; Parichatikanond, Warisara; Mangmool, Supachoke

doi:10.1016/j.lfs.2017.10.034

Cited by 49 publications

(40 citation statements)

References 45 publications

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“…2G). These data suggest that our in vitro 3D CTM model recapitulates previous in vivo studies demonstrating a cross-talk between CMs and ECs via VEGF [12,42]. This hypothesis is further strengthened as levels of VEGF were found to be increased in culture supernatants of PE stimulated CM monocultures compared to untreated CMs cultures (Fig.…”

Section: Pe Stimulation Augments Vascularization Of Ctmssupporting

confidence: 87%

Dissection of heterocellular cross-talk in vascularized cardiac tissue mimetics

Wagner

Pham

Nicin

et al. 2020

Journal of Molecular and Cellular Cardiology

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Cellular specialization and interaction with other cell types in cardiac tissue is essential for the coordinated function of cell populations in the heart. The complex interplay between cardiomyocytes, endothelial cells and fibroblasts is necessary for adaptation but can also lead to pathophysiological remodeling. To understand this complex interplay, we developed 3D vascularized cardiac tissue mimetics (CTM) to study heterocellular crosstalk in hypertrophic, hypoxic and fibrogenic environments. This 3D platform responds to physiologic and pathologic stressors and mimics the microenvironment of diseased tissue. In combination with endothelial cell fluorescence reporters, these cardiac tissue mimetics can be used to precisely visualize and quantify cellular and functional responses upon stress stimulation. Utilizing this platform, we demonstrate that stimulation of α/β-adrenergic receptors with phenylephrine (PE) promotes cardiomyocyte hypertrophy, metabolic maturation and vascularization of CTMs. Increased vascularization was promoted by conditioned medium of PE-stimulated cardiomyocytes and blocked by inhibiting VEGF or upon β-adrenergic receptor antagonist treatment, demonstrating cardiomyocyte-endothelial cross-talk. Pathophysiological stressors such as severe hypoxia reduced angiogenic sprouting and increased cell death, while TGF β2 stimulation increased collagen deposition concomitant to endothelial-to-mesenchymal transition. In sum, we have developed a cardiac 3D culture system that reflects native cardiac tissue function, metabolism and morphology-and for the first time enables the tracking and analysis of cardiac vascularization dynamics in physiology and pathology.

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Section: Pe Stimulation Augments Vascularization Of Ctmssupporting

confidence: 87%

Dissection of heterocellular cross-talk in vascularized cardiac tissue mimetics

Wagner

Pham

Nicin

et al. 2020

Journal of Molecular and Cellular Cardiology

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“…Gene deletion of GRK2 enhances survival, improves contractility, and inhibits cardiac remodeling in a mouse model of post-MI 63Treatment with β-blockers (e.g., atenolol, metoprolol, and propranolol) blocked the effects of βAR-mediated fibroblast activation (64) pathology is lacking and needs further investigation. Next, the signaling of TGF-β, excluding conclusions regarding specific isoforms, is discussed in detail.…”

Section: Tgf-β Signal Transductionmentioning

confidence: 99%

Therapeutic Targets for the Treatment of Cardiac Fibrosis and Cancer: Focusing on TGF-β Signaling

Parichatikanond

Luangmonkong

Mangmool

et al. 2020

Front. Cardiovasc. Med.

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106

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Transforming growth factor-β (TGF-β) is a common mediator of cancer progression and fibrosis. Fibrosis can be a significant pathology in multiple organs, including the heart. In this review, we explain how inhibitors of TGF-β signaling can work as antifibrotic therapy. After cardiac injury, profibrotic mediators such as TGF-β, angiotensin II, and endothelin-1 simultaneously activate cardiac fibroblasts, resulting in fibroblast proliferation and migration, deposition of extracellular matrix proteins, and myofibroblast differentiation, which ultimately lead to the development of cardiac fibrosis. The consequences of fibrosis include a wide range of cardiac disorders, including contractile dysfunction, distortion of the cardiac structure, cardiac remodeling, and heart failure. Among various molecular contributors, TGF-β and its signaling pathways which play a major role in carcinogenesis are considered master fibrotic mediators. In fact, recently the inhibition of TGF-β signaling pathways using small molecule inhibitors, antibodies, and gene deletion has shown that the progression of several cancer types was suppressed. Therefore, inhibitors of TGF-β signaling are promising targets for the treatment of tissue fibrosis and cancers. In this review, we discuss the molecular mechanisms of TGF-β in the pathogenesis of cardiac fibrosis and cancer. We will review recent in vitro and in vivo evidence regarding antifibrotic and anticancer actions of TGF-β inhibitors. In addition, we also present available clinical data on therapy based on inhibiting TGF-β signaling for the treatment of cancers and cardiac fibrosis.

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“…Our findings were consistent with previous reports that β2-AR agonist treatment increased the expression of α-SMA and COL1 in human cardiomyocytes and mouse liver. 24,39 Collagen is the most rich protein in vertebrate and contributes to maintaining the integrity of various tissues via the interaction with cell surfaces and other extracellular matrix molecules. 40 COL1, the fibril-forming collagen in PDL tissue, was suggested to perform primary roles in metabolism and homeostasis of PDL tissue because of its continuous and rapid turnover.…”

Section: Discussionmentioning

confidence: 99%

Functions of beta2‐adrenergic receptor in human periodontal ligament cells

Tomokiyo

Hasegawa

Yuda

et al. 2020

J of Cellular Biochemistry

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Adrenergic receptors (ARs) are receptors of noradrenalin and adrenalin, of which there are nine different subtypes. In particular, β2 adrenergic receptor (β2-AR) is known to be related to the restoration and maintenance of homeostasis in bone and cardiac tissues; however, the functional role of signaling through β2-AR in periodontal ligament (PDL) tissue has not been fully examined. In this report, we investigated that β2-AR expression in PDL tissues and their features in PDL cells. β2-AR expressed in rat PDL tissues and human PDL cells (HPDLCs) derived from two different patients (HPDLCs-2G and-3S). Rat PDL tissue with occlusal loading showed high β2-AR expression, while its expression was downregulated in that without loading. In HPDLCs, β2-AR expression was increased exposed to stretch loading. The gene expression of PDL-related molecules was investigated in PDL clone cells (2-23 cells) overexpressing β2-AR. Their gene expression and intracellular cyclic adenosine monophosphate (cAMP) levels were also investigated in HPDLCs treated with a specific β2-AR agonist, fenoterol (FEN). Overexpression of β2-AR significantly promoted the gene expression of PDL-related molecules in 2 to 23 cells. FEN led to an upregulation in the expression of PDL-related molecules and increased intracellular cAMP levels in HPDLCs. In both HPDLCs, inhibition of cAMP signaling by using protein kinase A inhibitor suppressed the FEN-induced gene expression of α-smooth muscle actin. Our findings suggest that the occlusal force is important for β2-AR expression in PDL tissue and β2-AR is involved in fibroblastic differentiation and collagen synthesis of PDL cells. The signaling through β2-AR might be important for restoration and homeostasis of PDL tissue.

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Sustained β-AR stimulation induces synthesis and secretion of growth factors in cardiac myocytes that affect on cardiac fibroblast activation

Cited by 49 publications

References 45 publications

Dissection of heterocellular cross-talk in vascularized cardiac tissue mimetics

Dissection of heterocellular cross-talk in vascularized cardiac tissue mimetics

Therapeutic Targets for the Treatment of Cardiac Fibrosis and Cancer: Focusing on TGF-β Signaling

Functions of beta2‐adrenergic receptor in human periodontal ligament cells

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