cAMP Inhibits Transforming Growth Factor-β-Stimulated Collagen Synthesis via Inhibition of Extracellular Signal-Regulated Kinase 1/2 and Smad Signaling in Cardiac Fibroblasts

Liu, Xiaoqiu; Sun, Shu Qiang; Hassid, Aviv; Ostrom, Rennolds S.

doi:10.1124/mol.106.028951

Cited by 121 publications

(92 citation statements)

References 43 publications

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“…However, we previously showed that Ang-(1-7) increased cyclic AMP (cAMP) in VSMCs; (33) because an increase in cAMP inhibited TGF-β-stimulated collagen synthesis by ERK1/2 signaling in cardiac fibroblasts (34), Ang-(1-7) may increase cAMP in tumoral fibroblasts to reduce TGF-β. In addition, the DUSP1 promoter contains a cAMP-responsive element (35), suggesting that Ang-(1-7) may increase cAMP in tumoral fibroblasts to upregulate DUSP1, reduce MAPK activities, and inhibit fibrosis.…”

Section: Discussionmentioning

confidence: 99%

Angiotensin-(1-7) Reduces Fibrosis in Orthotopic Breast Tumors

et al. 2010

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Angiotensin-(1-7) ] is an endogenous 7-amino acid peptide hormone of the renin-angiotensin system that has antiproliferative properties. In this study, Ang-(1-7) inhibited the growth of cancer-associated fibroblasts (CAF) and reduced fibrosis in the tumor microenvironment. A marked decrease in tumor volume and weight was observed in orthotopic human breast tumors positive for the estrogen receptor (BT-474 or ZR-75-1) and HER2 (BT-474) following Ang-

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Section: Discussionmentioning

confidence: 99%

Angiotensin-(1-7) Reduces Fibrosis in Orthotopic Breast Tumors

et al. 2010

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“…18 Similarly, the activation of Smad3 is repressed by increases in intracellular cAMP. 19 In contrast, Smad pathways are activated by molecules such as IGFBP-3, NO donors, and advanced glycation end products, probably through the transactivation of TGF␤ type I receptor. 20 Finally, there are conflicting data on the possible regulatory action of ERK-1,2; these kinases are known to phosphorylate certain R-Smads at their linker regions, and positive and negative regulatory effects on the Smad pathway have been reported.…”

Section: Introductionmentioning

confidence: 99%

PGE2 induces angiogenesis via MT1-MMP–mediated activation of the TGFβ/Alk5 signaling pathway

Alfranca

López-Oliva

Genı́s

et al. 2008

Blood

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The development of a new vascular network is essential for the onset and progression of many pathophysiologic processes. Cyclooxygenase-2 displays a proangiogenic activity in in vitro and in vivo models, mediated principally through its metabolite prostaglandin E 2 (PGE 2 ). Here, we provide evidence for a novel signaling route through which PGE 2 activates the Alk5-Smad3 pathway in endothelial cells. PGE 2 induces Alk5-dependent Smad3 nuclear translocation and DNA binding, and the activation of this pathway involves the release of active TGF␤ from its latent form through a process mediated by the metalloproteinase MT1-MMP, whose membrane clustering is promoted by PGE 2 . MT1-MMP-dependent transforming growth factor ␤ (TGF␤) signaling through Alk5 is also required for PGE 2 -induced endothelial cord formation in vitro, and Alk5 kinase activity is required for PGE 2 -induced neovascularization in vivo. These findings identify a novel signaling pathway linking PGE 2 and TGF␤, 2 effectors involved in tumor growth and angiogenesis, and reveal potential targets for the treatment of angiogenesis-related disorders. (Blood. 2008; 112:1120-1128) IntroductionGrowth of new vessels to ensure the supply of oxygen and nutrients to tissues is required for the establishment and progression of a variety of pathophysiologic situations, such as tumor development and metastasis, chronic inflammatory diseases, and vascular retinopathies. In the adult, this is achieved mainly by angiogenesis, in which new vessels grow out from a preformed vascular system. The formation of new capillaries by endothelial cells (ECs) is regulated by an exquisite balance between pro-and antiangiogenic factors. 1 A number of proangiogenic factors have been shown to increase the expression of cyclooxygenase-2 (COX-2). 2 COX-2 is an oxygenase that catalyzes the conversion of arachidonic acid to prostaglandin H 2 , which is in turn metabolized by diverse specific terminal synthases to form distinct prostanoids (prostaglandins and thromboxanes). 3 Evidence supporting the involvement of COX-2 in angiogenesis includes the impairment of neovessel formation in COX-2 knockout (KO) mice and the fact that specific COX-2 inhibitors block angiogenesis-like processes in in vitro and in vivo models. 3 A major product of COX-2 activity is prostaglandin E 2 (PGE 2 ). PGE 2 signals via 4 G-protein-coupled receptors (GPCR), named EP1 to EP4. These receptors each signal through distinct G-protein subunits, thereby initiating diverse downstream signaling pathways. EP1 usually couples to Gq, which activates PLC␥ to produce an increase in intracellular calcium concentration. EP2 and EP4 couple to Gs, with subsequent activation of PKA and increased cAMP synthesis. In contrast, signaling via EP3 often results in decreased cAMP concentrations, owing to the receptor coupling to Gi subunits. 4 In addition to these receptors, PGE 2 transactivates tyrosine kinase receptors, either through intracellular mechanisms or, in the case of epidermal growth factor receptor, through the metallo...

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“…Recent studies suggest that the TGF-␤1/Smad pathway can be regulated by the MEK-ERK1/2 pathway. 33 We further investigated the effects of MEK-ERK1/2 activation on fibrosis and found that blocking MEK-ERK1/2 activation results in significant inhibition, whereas activation of MEK-ERK1/2 resulted in upregulation of collagen synthesis, as well as Smad 2 phosphorylation and Smad 2/3 translocation. The results indicate that cFLIP blocks cardiac fibrosis by inhibiting the MEK-ERK1/2 pathway.…”

Section: Et Al Cflip Inhibits Cardiac Hypertrophymentioning

confidence: 99%

Cellular FLICE-Inhibitory Protein Protects Against Cardiac Remodeling Induced by Angiotensin II in Mice

Tang²,

Liu³

et al. 2010

Hypertension

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Abstract-The development of cardiac hypertrophy in response to increased hemodynamic load and neurohormonal stress is initially a compensatory response that may eventually lead to ventricular dilatation and heart failure. Cellular FLICE-inhibitory protein (cFLIP) is a homologue of caspase 8 without caspase activity that inhibits apoptosis initiated by death receptor signaling. Previous studies showed that cFLIP expression was markedly decreased in the ventricular myocardium of patients with end-stage heart failure. However, the critical role of cFLIP on cardiac remodeling remains unclear. To specifically determine the role of cFLIP in pathological cardiac remodeling, we used heterozygote cFLIP ϩ/Ϫ mice and transgenic mice with cardiac-specific overexpression of the human cFLIP L gene. Our results demonstrated that the cFLIP ϩ/Ϫ mice were susceptible to cardiac hypertrophy and fibrosis through inhibition of mitogen-activated protein kinase kinase-extracellular signal-regulated kinase 1/2 signaling, whereas the transgenic mice displayed the opposite phenotype in response to angiotensin II stimulation. These studies indicate that cFLIP protein is a crucial component of the signaling pathway involved in cardiac remodeling and heart failure.

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cAMP Inhibits Transforming Growth Factor-β-Stimulated Collagen Synthesis via Inhibition of Extracellular Signal-Regulated Kinase 1/2 and Smad Signaling in Cardiac Fibroblasts

Cited by 121 publications

References 43 publications

Angiotensin-(1-7) Reduces Fibrosis in Orthotopic Breast Tumors

Angiotensin-(1-7) Reduces Fibrosis in Orthotopic Breast Tumors

PGE2 induces angiogenesis via MT1-MMP–mediated activation of the TGFβ/Alk5 signaling pathway

Cellular FLICE-Inhibitory Protein Protects Against Cardiac Remodeling Induced by Angiotensin II in Mice

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