Altered collagen homeostasis in human aortic smooth muscle cells (HAoSMCs) induced by aldosterone

Gekle, Michael; Mildenberger, Sigrid; Freudinger, Ruth; Großmann, Claudia

doi:10.1007/s00424-007-0211-9

Cited by 28 publications

(23 citation statements)

References 53 publications

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“…These data are in agreement with some in vitro studies 23,43,44 but are in contrast to other studies 45,46 that failed to demonstrate a direct effect of aldosterone on collagen production. This disagreement may be related to cell-and species-specific differences or to variations in culture conditions.…”

Section: Discussionsupporting

confidence: 91%

Aldosterone Induces Elastin Production in Cardiac Fibroblasts through Activation of Insulin-Like Growth Factor-I Receptors in a Mineralocorticoid Receptor-Independent Manner

Bunda

Liu

Wang

et al. 2007

The American Journal of Pathology

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Aldosterone is known to regulate electrolyte homeostasis, but it may also contribute to other processes, including the maladaptive remodeling of postinfarct hearts. Because aldosterone has been implicated in the stimulation of collagen production in the heart, we investigated whether it would also affect elastin deposition in cultures of human cardiac fibroblasts. We first demonstrated that treatment with 1 to 50 nmol/L aldosterone leads to a significant increase in collagen type I mRNA levels and in subsequent collagen fiber deposition. Pretreatment of cells with the mineralocorticoid receptor antagonist spironolactone, but not with the glucocorticoid receptor antagonist RU 486, inhibited collagen synthesis in aldosterone-treated cultures. Most importantly, we demonstrated that aldosterone also increases elastin mRNA levels, tropoelastin synthesis, and elastic fiber deposition in a dose-dependent manner. Strikingly, neither spironolactone nor RU 486 eliminated aldosterone-induced increases in elastin production. We further discovered that the proelastogenic effect of aldosterone involves a rapid increase in tyrosine phosphorylation of the insulin-like growth factor-I receptor and that the insulin-like growth factor-I receptor kinase inhibitor AG1024 or an anti-insulin-like growth factor-I receptor-neutralizing antibody inhibits both insulin-like growth factor-I and aldosterone-induced elastogenesis. Thus, we have demonstrated for the first time that aldosterone, which stimulates collagen production through the mineralocorticoid receptor-dependent pathway, also increases elastogenesis via a parallel mineralocorticoid receptor-independent pathway involving I insulin-like growth factor-I receptor signaling.

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Section: Discussionsupporting

confidence: 91%

Aldosterone Induces Elastin Production in Cardiac Fibroblasts through Activation of Insulin-Like Growth Factor-I Receptors in a Mineralocorticoid Receptor-Independent Manner

Bunda

Liu

Wang

et al. 2007

The American Journal of Pathology

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“…Determination of Extracellular Collagen III Abundance by ELISA-Collagen III abundance in the medium of CHO cells expressing HER1 (55) was determined by ELISA as described previously (51). We tested the cross-reactivity of the primary antibodies (1:1000; Biotrend, Köln, Germany) using collagen standards and did not observe any significant cross-reactivity.…”

Section: Methodsmentioning

confidence: 99%

EF Domains Are Sufficient for Nongenomic Mineralocorticoid Receptor Actions

Großmann

Freudinger

Mildenberger

et al. 2008

Journal of Biological Chemistry

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The mineralocorticoid receptor (MR) is important for salt homeostasis and reno-cardiovascular pathophysiology. Signaling mechanisms include, besides classical genomic pathways, nongenomic pathways with putative pathophysiological relevance involving the mitogen-activated protein kinases ERK1/2. We determined the MR domains required for nongenomic signaling and their potential to elicit pathophysiological effects in cultured cells under defined conditions. The expression of fulllength human MR or truncated MR consisting of the domains CDEF (MR CDEF ), DEF (MR DEF ), or EF (MR EF ) renders cells responsive for the MR ligand aldosterone with respect to nongenomic ERK1/2 phosphorylation, whereas only full-length MR and MR CDEF conferred genomic responsiveness. ERK1/2 phosphorylation depends on the EGF receptor and cSRC kinase. MR EF expression is sufficient to evoke the aldosterone-induced increase of collagen III levels, similar to full-length MR expression. Our data suggest that nongenomic MR signaling is mediated by the EF domains and present the first proof of principle showing that nongenomic signaling can be sufficient for some pathophysiological effects. The minimum amino acid motif required for nongenomic MR signaling and its importance in various effects have yet to be determined. The mineralocorticoid receptor (MR)2 is usually described as a ligand-inducible transcription factor that controls expression of target genes involved in the regulation of Na ϩ and K ϩ homeostasis as well as blood pressure regulation (1). MR also promotes cardiovascular and renal fibrosis caused by tissue remodeling as well as endothelial dysfunction, independent of its effects on blood pressure or NaCl homeostasis (2-4). The activation of MR modulates the expression of various proteins like the epithelial sodium channel, Na ϩ -K ϩ -ATPase, the SGK kinase, and the EGF receptor (1, 5-7). There is increasing evidence that not all biological effects of MR are mediated by direct DNA binding and control of target gene expression (8, 9). Some actions of MR appear to be the result of a cross-talk with other signaling cascades, such as nongenomic regulation of intracellular calcium (10, 11), protein kinase C, cSRC kinase, EGF receptor (EGFR) activity, or extracellular-regulated kinase (ERK1/2) (12-15). Furthermore, there seems to exist a functional cross-talk between classical and nongenomic actions (9, 16 -18).The classical receptors for estrogen (ER), progesterone (PR), androgens (AR), and glucocorticoids (GR) also contribute to the nongenomic effects (12, 14, 19 -26) of these hormones, in many cases via ERK1/2 kinases. Some nongenomic effects arise from classical receptors in or at the plasma membrane (e.g. ER, Ref. 13) but specialized membrane receptors, like mPR and GPR30 have also been described (27, 28). However, the results for the specialized membrane receptors are controversial (29, 30). The mechanism(s) of action for ER and PR as well as the receptor domains involved have been explored in more detail. Receptor domains D, E, a...

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“…12 Increases in EGFR expression and/or activation have been demonstrated after aldo stimulation, ex vivo after the incubation of rat aorta and renal, endothelial, and vascular smooth muscle cultured cells with aldo and in vivo in the aorta of adrenalectomized rats treated with aldo. [13][14][15][16] However, the consequences of EFGR activation to the vascular effects of aldo have not yet been demonstrated in vivo.We hypothesized that EGFR activation might contribute to the damaging effects of aldo in the vasculature in vivo. We analyzed the molecular and functional vascular consequences of Received March 29, 2010; first decision April 19, 2010; accepted September 14, 2010 …”

mentioning

confidence: 99%

mentioning

confidence: 99%

Epidermal Growth Factor Receptor Mediates the Vascular Dysfunction But Not the Remodeling Induced by Aldosterone/Salt

et al. 2011

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Abstract-Pathophysiological aldosterone (aldo)/mineralocorticoid receptor signaling has a major impact on the cardiovascular system, resulting in hypertension and vascular remodeling. Mineralocorticoids induce endothelial dysfunction, decreasing vasorelaxation in response to acetylcholine and increasing the response to vasoconstrictors. Activation of the epidermal growth factor receptor (EGFR) is thought to mediate the vascular effects of aldo, but this has yet to be demonstrated in vivo. In this study, we analyzed the molecular and functional vascular consequences of aldo-salt challenge in the waved 2 mouse, a genetic model with a partial loss of EGFR tyrosine kinase activity. Deficient EGFR activity is associated with global oxidative stress and endothelial dysfunction. A decrease in EGFR activity did not affect the arterial wall remodeling process induced by aldo-salt. By contrast, normal EGFR activity was required for the aldo-induced enhancement of phenylephrine-and angiotensin II-mediated vasoconstriction. In conclusion, this in vivo study demonstrates that EGFR plays a key role in aldosterone-mediated vascular reactivity. Clinical trials (Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study and Randomized Aldactone Evaluation Study) have demonstrated the beneficial effects of administering low doses of pharmacological antagonists of the mineralocorticoid receptor (MR; the receptor of the mineralocorticoid hormone aldosterone [aldo]) to patients with heart failure, with improvements in survival rate and morbidity. 1,2 These clinical benefits may partly result from improved vascular function. 3 The MR is expressed in both endothelium and smooth muscle, 4 and the vessels are now considered to be direct targets of aldo. 5 In the mouse, the 11␤-hydroxysteroid dehydrogenase type II enzyme is expressed in the endothelium but not in the smooth muscle, 4,6 at variance with humans. 7 Therefore, in the mouse, aldo is the specific ligand of the MR in the endothelium but not in the smooth muscle, where glucocorticoids could also activate MR. MR activation affects endothelial function and vascular tone: aldo infusion induces endothelial dysfunction, decreasing vasorelaxation in response to acetylcholine (Ach), and increasing the response to various vasoconstrictors. 5,8,9 We showed recently that an increase in MR signaling in the endothelium is associated with an increase in blood pressure and altered vascular tone. 4 Moreover, patients with primary aldosteronism have a higher aortic wall thickness than those with primary hypertension. 10 Aldo is, thus, recognized as a cardiovascular risk factor that exacerbates vascular injury, 3 although the underlying mechanisms remain unclear.It has been suggested that the epidermal growth factor receptor (EGFR) could play a key role in the cardiovascular effects of aldo. 11 In cultured cells, downstream EGFR signaling cascades are induced by aldo or prevented by MR blockade on aldo stimulation. 12 Increases in EGFR expression and/or activation have...

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Altered collagen homeostasis in human aortic smooth muscle cells (HAoSMCs) induced by aldosterone

Cited by 28 publications

References 53 publications

Aldosterone Induces Elastin Production in Cardiac Fibroblasts through Activation of Insulin-Like Growth Factor-I Receptors in a Mineralocorticoid Receptor-Independent Manner

Aldosterone Induces Elastin Production in Cardiac Fibroblasts through Activation of Insulin-Like Growth Factor-I Receptors in a Mineralocorticoid Receptor-Independent Manner

EF Domains Are Sufficient for Nongenomic Mineralocorticoid Receptor Actions

Epidermal Growth Factor Receptor Mediates the Vascular Dysfunction But Not the Remodeling Induced by Aldosterone/Salt

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