Response of adrenomedullin system to cytokine in cardiac fibroblasts?role of adrenomedullin as an antifibrotic factor

Nishikimi, Toshio; Akimoto, Kazumi; Mori, Yoshihide; Ishikawa, Yuichi; Ishimura, Kimihiko; Horio, Takeshi; Kangawa, Kenji; Matsuoka, Hiroaki

doi:10.1016/j.cardiores.2004.12.015

Cited by 14 publications

(10 citation statements)

References 40 publications

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“…The AM level per 10 5 cells was ϳ250 fmol/12 h in adipocytes, which was almost consistent with the previous report by Li et al (15), who stimulated 3T3-L1cells adipocytes by TNF-␣ (15). However, these values are considerably higher compared with those in cultured rat endothelial cells (ϳ20 fmol/12 h), vascular smooth muscle cells (ϳ5 fmol/12 h), cardiac fibroblasts (ϳ35 fmol/12 h), myocytes (ϳ20 fmol/12 h), human skin fibroblasts (ϳ100 fmol/12 h), and human lung fibroblasts (ϳ100 fmol/12 h) (9,10,15,32,36). Thus, the higher levels of the active form of AM in the medium of differentiated adipocytes suggest the role of endogenous AM in lipid metabolism in adipocytes.…”

Section: Discussionmentioning

confidence: 90%

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Role of adrenomedullin system in lipid metabolism and its signaling mechanism in cultured adipocytes

Iemura-Inaba¹,

Nishikimi²,

Akimoto³

et al. 2008

American Journal of Physiology-Regulatory, Integrative and Comp

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.-We investigated the levels of adrenomedullin (AM) system during the process of preadipocyte differentiation and its role in lipid metabolism and cellular signaling mechanism in differentiated adipocytes. We cultured rat preadipocytes and measured the following during the process of differentiation: two molecular forms of AM in the culture medium using a specific immunoradiometric assay and gene expression of AM and its receptor component using RT-PCR analysis. In differentiated adipocytes, we measured the effects of AM on the intracellular cAMP level, lipolysis, glucose incorporation, and the protein levels. Two molecular forms of AM were secreted into the medium, and the AM-mature/AM-total ratio was increased after 6 days of differentiation. Cultured rat preadipocytes highly expressed the genes of AM and its receptor components at day 1, and they increased at day 10. Administration of AM to preadipocytes increased the number of Oil Red O-positive adipocytes and spectrophotometric absorbance of Oil Red O. AM dose dependently increased cAMP level and lipolysis, and its effect was blocked by CGRP(8-37). Isoproterenol increased lipolysis, and AM had additive effects on isoproterenol-induced lipolysis. KT5720 and U0126 significantly inhibited the AM-induced lipolysis, whereas KT5720, but not U0126, significantly inhibited the isoproterenol-induced lipolysis. AM increased glucose incorporation and its effect was blocked by wortmannin. Western blot analysis revealed that AM increased phospho PKA, ERK, and Akt. These results indicate that AM and its receptor component are highly expressed in cultured adipocytes and may play a role in lipid metabolism via a different signaling pathway.adipocyte; calcitonin receptor like receptor; receptor activity-modifying proteins; lipolysis ADRENOMEDULLIN (AM) IS A POTENT hypotensive peptide that consists of 52 amino acids with an intramolecular disulfide bond and shares slight homology with calcitonin gene-related peptide (12). AM acts through seven-transmembrane domain G protein-coupled receptor, calcitonin receptor-like receptor (CLR), which associate with the receptor activity-modifying proteins (RAMP) 2 and RAMP 3 (17). AM circulates in human plasma, and the plasma AM concentration is increased in patients with cardiovascular diseases, including hypertension, renal failure, heart failure, and myocardial infarction, in proportion to the severity of the disease (7,19,31). AM messenger RNA is highly expressed in the kidneys, lung, vasculature, and cardiac ventricles (12). AM is considered to act as an autocrine and/or paracrine factor, and increased AM in various pathological conditions exerts cardiorenoprotective effects via antiapoptotic, anti-inflammatory, and antioxidative actions (8,22,28). These facts suggest that AM is involved in the regulation of the cardiovascular system.Recent studies demonstrated that rat adipose tissue contains AM mRNA (14, 23), and adipose tissue obtained from rats fed a high-fat diet expresses greater amounts of AM than that obtained from rats fed ...

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Section: Discussionmentioning

confidence: 90%

“…One milliliter of the conditioned medium of the adipocytes incubated in a 10-cm dish was collected at 2, 4, 6, 8, and 10 days after the cells were transferred to differentiation medium (32). Each sample of conditioned medium was boiled for 10 min after the addition of one-tenth volume of 1 mol/l acetic acid to inactivate intrinsic proteases.…”

Section: Methodsmentioning

confidence: 99%

Role of adrenomedullin system in lipid metabolism and its signaling mechanism in cultured adipocytes

Iemura-Inaba¹,

Nishikimi²,

Akimoto³

et al. 2008

American Journal of Physiology-Regulatory, Integrative and Comp

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“…The relevance of these subtle RAMP2 and 3 changes in response to elevated AM in the cellular environment requires investigation, however altered sensitivity to AM may assist cells in recognizing an inflammatory environment [15,34] or contribute to a protective autocrine mechanism [27,35]. Furthermore, the apparent association of certain RAMPs, and hence receptors, with particular stimulation states is of interest, as investigated in other cell types and conditions [12] such as up-regulation of only RAMP3 was reported in rat lungs [36], while up-regulation of CLR, RAMP2 and RAMP3 was detected in rat heart [37].…”

Section: Discussionmentioning

confidence: 95%

Adrenomedullin receptors on human T cells are glucocorticoid-sensitive

Liverani

McLeod

Paul

2012

International Immunopharmacology

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Adrenomedullin (AM) is a novel vasodilatatory peptide which acts primarily through the calcitonin receptor-like receptor (CLR) in combination with either receptor-activity-modifying-protein (RAMP) 2 or 3 (forming receptors, AM(1) and AM(2) respectively). AM plays an important role during inflammation, with its expression increasing following cytokine treatment, promoting macrophage action in situ and high expression by T cells during hypoxic conditions. Examination of T cell AM receptor expression has previously been incomplete, hence we here consider the presentation of AM receptors and their responsiveness to AM and glucocorticoids (GC). AM receptor expression was examined by PCR and flow cytometry in primary human T cells, revealing that RAMP2, 3 and CLR are physiologically expressed in unstimulated T cells, both intracellularly and on the cell surface. PHA stimulation decreased receptor proteins, significantly so for CLR and RAMP3. Incubation with AM elicited limited receptor alterations however, GC treatment (10(-6) M; 24 h) markedly affected cell surface expression, significantly increasing receptor components in unstimulated cells and significantly decreasing the same in stimulated T cells. Our findings indicate that human T cells utilize both AM(1) and AM(2) receptors, which are GC-sensitive in an activation-state dependent manner.

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“…15,16 Sub-cultured fibroblasts from passages 4 to 6 were used in this experiment, and they were Ͼ99% positive for immunostaining with vimentin antibody. In addition, they were negative for desmin (for myocytes), smooth muscle actin (for vascular smooth muscle cells), and a polyclonal antibody against von Willebrand factor (for endothelial cells).…”

Section: Cell Culturementioning

confidence: 99%

Activation of AMP-Activated Protein Kinase Enhances Angiotensin II–Induced Proliferation in Cardiac Fibroblasts

et al. 2006

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Abstract-AMP-activated kinase (AMPK) is a highly conserved heterotrimeric kinase that functions as a metabolic regulator of cellular enzymes involved in carbohydrate and fat metabolism, which regulate ATP conservation and synthesis. Here, we investigated whether AMPK signaling has a role in the regulation of angiotensin II (Ang II)-induced proliferation in rat cardiac fibroblasts. Aminoimidazole-4-carboxamide-1-␤-ribofuranoside (AICAR) activated AMPK in rat cardiac fibroblasts and increased Ang II-induced extracellular signal-regulated kinase 1/2 phosphorylation and activity. AICAR also increased Ang II-induced c-fos mRNA expression in the cells. Key Words: cardiac function Ⅲ angiotensin Ⅲ hypertrophy Ⅲ signal transduction A MP-activated kinase (AMPK) is a highly conserved heterotrimeric kinase that functions as a metabolic regulator of cellular enzymes involved in carbohydrate and fat metabolism, which regulate ATP conservation and synthesis. 1 AMPK is activated by conditions that increase the AMP:ATP ratio, such as exercise and metabolic stress. AMPK has been most extensively examined under conditions of stress, such as exercise and hypoxia-ischemia. When the AMP:ATP ratio increases, AMPK is activated by AMPK kinase to combine with AMP, thus inducing a conformational change and decreasing the AMP:ATP ratio by switching off ATP-consuming pathways and switching on ATP-generating pathways. 1 Considerable information exists regarding the regulation of AMPK activation in a variety of cell types, including cardiac cells. 2,3 There is a correlation between AMPK activation and the development of cardiac hypertrophy. 4,5 Pressure overload-induced hypertrophic cardiomyopathy is associated with increased AMPK activity. 4 In addition, AMPK plays a role in familial Wolff-Parkinson-White syndrome and hypertrophic cardiomyopathy via mutations in PRKAG2, a gene encoding the ␥2 subunit of AMPK. 6 -8 On the other hand, recent evidence indicates that AMPK activation inhibits proteins synthesis 9,10 and might, thus, be expected to reduce the development of hypertrophy. Although much has been learned about the role of AMPK in the development of cardiac hypertrophy, the molecular mechanism by which AMPK regulates cardiac hypertrophy is still unclear.Interstitial fibroblast proliferation and collagen accumulation is associated with compensatory remodeling of the hypertrophic myocardium, 11,12 and structural remodeling leads to diastolic and systolic dysfunction. 13 Angiotensin (Ang) II is closely involved in cardiac remodeling by stimulating hyperplastic growth of cardiac fibroblasts 14 and the synthesis of extracellular matrix proteins. 12 Therefore, we investigated the role of AMPK in cardiac remodeling using cardiac fibroblasts. We used 5-aminoimidazole-4-carboxamide-1-␤-ribofuranoside (AICAR), which is an adenosine analog, as well as cell-permeable activator of AMPK and a small interfering RNA (siRNA) for AMPK, which is an AMPK inhibitor. We examined the effects of both the AMPK activator and inhibitor on the extracellular sign...

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Response of adrenomedullin system to cytokine in cardiac fibroblasts?role of adrenomedullin as an antifibrotic factor

Abstract: These results provide evidence that the adrenomedullin system acts as an autocrine antifibrotic factor in the regulation of collagen synthesis in cardiac fibroblasts exposed to higher cytokine levels. This may beneficially modulate the pathophysiology of certain cardiac diseases.

Cited by 14 publications

References 40 publications

Role of adrenomedullin system in lipid metabolism and its signaling mechanism in cultured adipocytes

Role of adrenomedullin system in lipid metabolism and its signaling mechanism in cultured adipocytes

Adrenomedullin receptors on human T cells are glucocorticoid-sensitive

Activation of AMP-Activated Protein Kinase Enhances Angiotensin II–Induced Proliferation in Cardiac Fibroblasts

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