Participation of aldosterone in the vascular inflammatory response of spontaneously hypertensive rats: role of the NFκB/IκB system

Sanz-Rosa, David; Cediel, Eva; Heras, Natalia de las; Miana, María; Balfagón, Gloria; Lahera, Vicente; Cachofeiro, Victoria

doi:10.1097/01.hjh.0000170379.08214.5a

Cited by 51 publications

(46 citation statements)

References 35 publications

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“…29 In spontaneously hypertensive rats, eplerenone decreases aortic expression of IL-1β, IL-6, and tumor necrosis factor-α as well as plasma levels of IL-1β and IL-6, likely through upregulation of IκB expression and downregulation of NF-κB expression. 30 In renal collecting duct cells, aldosterone works through an MR-SGK1/NF-κB pathway to promote expression of NF-κB target genes, including IL-1β and IL-6. 31 Similar pathway has been reported in mesangial cells.…”

Section: Discussionmentioning

confidence: 99%

Mineralocorticoid Receptor Deficiency in Macrophages Inhibits Neointimal Hyperplasia and Suppresses Macrophage Inflammation Through SGK1-AP1/NF-κB Pathways

Sun

Shen

et al. 2016

ATVB

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Objective-Restenosis after percutaneous coronary intervention remains to be a serious medical problem. Although mineralocorticoid receptor (MR) has been implicated as a potential target for treating restenosis, the cellular and molecular mechanisms are largely unknown. This study aims to explore the functions of macrophage MR in neointimal hyperplasia and to delineate the molecular mechanisms. Approach and Results-Myeloid MR knockout (MMRKO) mice and controls were subjected to femoral artery injury.MMRKO reduced intima area and intima/media ratio, Ki67-and BrdU-positive vascular smooth muscle cells, expression of proinflammatory molecules, and macrophage accumulation in injured arteries. MMRKO macrophages migrated less in culture. MMRKO decreased Ki67-and BrdU-positive macrophages in injured arteries. MMRKO macrophages were less Ki67-positive in culture. Conditioned media from MMRKO macrophages induced less migration, Ki67 positivity, and proinflammatory gene expression of vascular smooth muscle cells. After lipopolysaccharide treatment, MMRKO macrophages had decreased p-cFos and p-cJun compared with control macrophages, suggesting suppressed activation of activator protein-1 (AP1). Nuclear factor-κB (NF-κB) pathway was also inhibited by MMRKO, manifested by decreased p-IκB kinase-β and p-IκBα, increased IκBα expression, decreased nuclear translocation of p65 and p50, as welll as decreased phosphorylation and expression of p65. Finally, overexpression of serum-and-glucocorticoid-induciblekinase-1 (SGK1) attenuated the effects of MR deficiency in macrophages. This manuscript was sent to Kathryn Moore, Consulting Editor, for review by expert referees, editorial decision, and final disposition. *These authors contributed equally to this article. angioplasty of coronary arteries and neointima formation after stent implantation in coronary arteries of swine. 3,4 However, the effects of MR antagonists on restenosis in human patients are uncertain. Early study has shown that spironolactone, another antagonist of MR, does not change the incidence of restenosis at 6 months after stenting in a clinical trial. Conclusions-Selective5 More recent results, however, have demonstrated that spironolactone reduces the rate of repeat revascularization at 1 year after PCI.6 Different population, length of treatments, and end points between the 2 studies may have contributed to the differential results. More fundamental studies on the cellular and molecular mechanisms how MR is involved in restenosis are needed to provide new insights for ultimately using this target to treat restenosis.Recent studies using knockout mouse models have begun to reveal the cell type-specific influence of MR in the vasculature.7 MR in monocytes/macrophages may play important roles in neointimal hyperplasia. Myeloid MR knockout (MMRKO) mouse was established and used to study the functions of macrophage MR in the cardiovascular system. The data have illustrated the importance of macrophage MR in cardiac hypertrophy, fibrosis, and inflammation. [8][9][10]...

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Section: Discussionmentioning

confidence: 99%

Mineralocorticoid Receptor Deficiency in Macrophages Inhibits Neointimal Hyperplasia and Suppresses Macrophage Inflammation Through SGK1-AP1/NF-κB Pathways

Sun

Shen

et al. 2016

ATVB

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“…Full-length HA-p105 was from Dr. Ghosh (33), whereas the various deletion constructs of HAp105 have been described previously (34). HA-TPL2 constructs were from P. Tsichlis (35). HA-p105N antibody used for immunoprecipitating endogenous p105 has been described (36).…”

Section: Methodsmentioning

confidence: 99%

Arrestin-2 and G Protein-coupled Receptor Kinase 5 Interact with NFκB1 p105 and Negatively Regulate Lipopolysaccharide-stimulated ERK1/2 Activation in Macrophages

Parameswaran

Pao

Leonhard

et al. 2006

Journal of Biological Chemistry

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Toll-like receptors (TLRs) are a recently described receptor class involved in the regulation of innate and adaptive immunity. Here, we demonstrate that arrestin-2 and GRK5 (G protein-coupled receptor kinase 5), proteins that regulate G protein-coupled receptor signaling, play a negative role in TLR4 signaling in Raw264.7 macrophages. We find that lipopolysaccharide (LPS)-induced ERK1/2 phosphorylation is significantly enhanced in arrestin-2 and GRK5 knockdown cells. To elucidate the mechanisms involved, we tested the effect of arrestin-2 and GRK5 knockdown on LPS-stimulated signaling components that are upstream of ERK phosphorylation. Upon LPS stimulation, IB kinase promotes phosphorylation and degradation of NFB1 p105 (p105), which releases TPL2 (a MAP3K), which phosphorylates MEK1/2, which in turn phosphorylates ERK1/2. We demonstrate that knockdown of arrestin-2 leads to enhanced LPS-induced phosphorylation and degradation of p105, enhanced TPL2 release, and enhanced MEK1/2 phosphorylation. GRK5 knockdown also results in enhanced IB kinase-mediated p105 phosphorylation and degradation, whereas GRK2 and GRK6 knockdown have no effect on this pathway. In vitro analysis demonstrates that arrestin-2 directly binds to the COOH-terminal domain of p105, whereas GRK5 binds to and phosphorylates p105. Taken together, these results suggest that p105 phosphorylation by GRK5 and binding of arrestin-2 negatively regulates LPS-stimulated ERK activation. These results reveal that arrestin-2 and GRK5 are important negative regulatory components in TLR4 signaling.Pathogen-associated molecular patterns in microbes serve as ligands to activate a recently described class of pattern recognition receptors called Toll-like receptors (TLRs).3 13 TLRs have been identified to date, with TLR1, -2, -4, -5, -6, and -11 displayed on the cell surface and TLR3, -7, -8, and -9 localized intracellularly (1). Activation of TLR signaling constitutes one of the earliest responses of an organism to microbe invasion and understanding the signaling pathways stimulated by these TLRs is an area of intense interest. The TLRs as well as interleukin receptors have a conserved ϳ200-amino acid region in their cytoplasmic tails, known as the Toll/interleukin-1 receptor domain. Within the TIR domain are conserved regions that are crucial for signaling. After ligand binding, the TLRs dimerize and undergo conformational changes that are required for the recruitment of downstream signaling molecules (2). These include the adaptor molecule Myd88 (myeloid differentiation primary response protein 88), interleukin-1 receptor-associated kinases, TAK1 (transforming growth factor-␤-activated kinase), TAK1-binding protein (TAB1 and -2), and TRAF-6 (tumor necrosis factor (TNF) receptor-associated factor 6) (3-6).TLRs primarily activate two major signaling pathways, nuclear factor -B (NFB) and mitogen-activated protein kinase (ERK, JNK, and p38) pathways. The NFB pathway results in activation of transcription factors that are thought to act as a "master switch" for inf...

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“…Both, osterix and Cbfa1 are upregulated in vessels of dialysis patients, indicative of osteogenic remodeling in these patients (22). Klotho is capable of reducing the vascular effects of Tnf-α (23), while aldosterone was shown to upregulate vascular Tnfa (24). Klotho itself also plays a role in maintaining vascular smooth muscle cell homeostasis in response to phosphate (6).…”

Section: Introductionmentioning

confidence: 99%

“…Aldosterone fosters cardiac fibrosis (29) and endothelial dysfunction (30), cardiovascular disorders commonly observed in CKD (4,5,31,32). Aldosterone increases Tnfa expression and subsequent NF-kB activation (24,30). Vascular smooth muscle cells express the aldosterone-sensitive mineralocorticoid (MR) receptor (33), and MR receptor activation stimulates vascular calcification (34).…”

Section: Introductionmentioning

confidence: 99%

Spironolactone ameliorates PIT1-dependent vascular osteoinduction in klotho-hypomorphic mice

et al. 2013

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Klotho is a potent regulator of 1,25-hydroxyvitamin D3 [1,25(OH) 2 D 3 ] formation and calcium-phosphate metabolism. Klotho-hypomorphic mice (kl/kl mice) suffer from severe growth deficits, rapid aging, hyperphosphatemia, hyperaldosteronism, and extensive vascular and soft tissue calcification. Sequelae of klotho deficiency are similar to those of end-stage renal disease. We show here that the mineralocorticoid receptor antagonist spironolactone reduced vascular and soft tissue calcification and increased the life span of kl/kl mice, without significant effects on 1,25(OH) 2 D 3 , FGF23, calcium, and phosphate plasma concentrations. Spironolactone also reduced the expression of osteoinductive Pit1 and Tnfa mRNA, osteogenic transcription factors, and alkaline phosphatase (Alpl) in calcified tissues of kl/kl mice. In human aortic smooth muscle cells (HAoSMCs), aldosterone dose-dependently increased PIT1 mRNA expression, an effect paralleled by increased expression of osteogenic transcription factors and enhanced ALP activity. The effects of aldosterone were reversed by both spironolactone treatment and PIT1 silencing and were mitigated by FGF23 cotreatment in HAoSMCs. In conclusion, aldosterone contributes to vascular and soft tissue calcification, an effect due, at least in part, to stimulation of spironolactone-sensitive, PIT1-dependent osteoinductive signaling.

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Participation of aldosterone in the vascular inflammatory response of spontaneously hypertensive rats: role of the NFκB/IκB system

Cited by 51 publications

References 35 publications

Mineralocorticoid Receptor Deficiency in Macrophages Inhibits Neointimal Hyperplasia and Suppresses Macrophage Inflammation Through SGK1-AP1/NF-κB Pathways

Mineralocorticoid Receptor Deficiency in Macrophages Inhibits Neointimal Hyperplasia and Suppresses Macrophage Inflammation Through SGK1-AP1/NF-κB Pathways

Arrestin-2 and G Protein-coupled Receptor Kinase 5 Interact with NFκB1 p105 and Negatively Regulate Lipopolysaccharide-stimulated ERK1/2 Activation in Macrophages

Spironolactone ameliorates PIT1-dependent vascular osteoinduction in klotho-hypomorphic mice

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