Influence of aldosterone on collagen synthesis and proliferation of rat cardiac fibroblasts

Rombouts, Krista; Wielant, Annemie; Hellemans, Karine; Schuppan, Detlef; Geerts, Albert

doi:10.1038/sj.bjp.0704247

Cited by 39 publications

(26 citation statements)

References 52 publications

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“…Although differences in total cardiac fibrosis between AS hi/hi and WT mice did not reach significance, our study revealed a significant increase in collagen III expression in AS hi/hi mice. Again, this is consistent with previous works by Rombouts et al 34 showing that low doses of aldosterone tend to increase procollagen III synthesis. Urinary excretion of 8-isoprostane, a marker of systemic oxidative stress, was significantly increased in the Ang II salt-treated AS hi/hi mice compared with WT mice, confirming the data of other investigators 35 that oxidative stress is involved in cardiac injury.…”

Section: Discussionsupporting

confidence: 82%

Salt-Sensitive Blood Pressure in Mice With Increased Expression of Aldosterone Synthase

et al. 2008

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Abstract-To study the effects of modestly increased expression of aldosterone synthase (AS), we generated mice (AS hi/hi ) by replacing the 3Ј untranslated region of AS mRNA with that from a stable mRNA. AS hi/hi mice on a normal-salt diet had 1.5 times the wild-type AS mRNA in adrenals, although their blood pressure and plasma aldosterone did not differ from wild-type mice. Changes in dietary salt did not affect the blood pressure of wild-type mice, but AS hi/hi mice had Ϸ10-mm Hg higher blood pressure on a high-salt diet than on a low-salt diet and than wild-type mice on either diet. The AS hi/hi mice on a high-salt diet also had higher plasma aldosterone, lower plasma potassium, and greater renal expression of the ␣ subunit of epithelial sodium channel compared with wild-type mice. The AS hi/hi mice on a high-salt diet also had more water intake and urine volume and less urine osmolality than wild-type mice. On a low-salt diet, AS hi/hi mice maintained normal blood pressure with less activation of the renin-angiotensin-aldosterone system than wild-type mice. The AS hi/hi mice also had less water intake and urine volume and higher urine osmolality than wild-type mice. On a medium high-salt diet, AS hi/hi mice were more susceptible than wild-type mice to infusion of angiotensin II, having a higher blood pressure, greater cardiac hypertrophy, and increased oxidative stress. Thus, a modest increase in AS expression makes blood pressure more sensitive to salt, suggesting that genetically increased AS expression in humans may contribute to hypertension and cardiovascular complications in societies with high-salt diets. Key Words: aldosterone synthase Ⅲ blood pressure Ⅲ dietary salt Ⅲ renin-angiotensin-aldosterone system Ⅲ water metabolism A n increasing body of data indicates that genetic susceptibility to essential hypertension is determined by small changes in many genes 1 rather by large changes in a few genes. 2 As a result, it is very difficult to establish a causative link between inherited differences in a candidate gene when studying human population, even when a strong correlation can be demonstrated. One approach to establish causation is to create differences in a candidate gene in mice and to ask whether blood pressure (BP) or other relevant parameters change. Here, we use this approach to determine the effect of modest increase in the expression of the gene cyp11b2, coding for aldosterone synthase (AS).Recent studies show that Ϸ10% of patients with essential hypertension have a high ratio of plasma aldosterone/plasma renin activity, suggesting some degree of inappropriately increased production of aldosterone. 3,4 Aldosterone plays an important role in controlling electrolyte homeostasis and BP, but it also has newly recognized effects in the remodeling of the heart, in abnormal vascular endothelial function, and in renal injury. 5 AS catalyzes the last step of aldosterone synthesis, and several investigators have published data suggesting that variations in the human AS gene (CYP11B2) may contrib...

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Section: Discussionsupporting

confidence: 82%

Salt-Sensitive Blood Pressure in Mice With Increased Expression of Aldosterone Synthase

et al. 2008

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“…40,41 This discrepancy may be because of the cell type, phenotype, and duration of aldosterone treatment. The advantage of our study is the use of human cardiac fibroblasts, which may be more closely related to a human condition than the rat cardiac fibroblasts used in the previous studies.…”

Section: Discussionmentioning

confidence: 99%

Aldosterone Induces Tissue Inhibitor of Metalloproteinases-1 Expression and Further Contributes to Collagen Accumulation

et al. 2016

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Abstract-Aldosterone induces myocardial fibrosis. Tissue inhibitor of metalloproteinases-1 (TIMP-1) is a key factor of myocardial fibrosis. This study tested the hypothesis that aldosterone induces TIMP-1 expression and contributes to the fibrotic process. We prospectively enrolled 54 patients with primary aldosteronism, and measured plasma TIMP-1 and echocardiographic parameters. In the cell study, we investigated the possible molecular mechanism by which aldosterone induces TIMP-1 secretion and the effects on collagen accumulation. In the animal study, we measured serum TIMP-1 levels, cardiac TIMP-1 levels, and cardiac structure in an aldosterone infusion mouse model using implantation of aldosterone pellets. In patients with primary aldosteronism, plasma TIMP-1 was correlated with 24-hour urinary aldosterone, left ventricular mass, and impairment of left ventricular diastolic function. In human cardiac fibroblasts, TIMP-1 protein and mRNA expressions were significantly increased by aldosterone through the glucocorticoid receptor/PI3K/Akt/nuclear factor-κB pathway. TIMP-1 small-interfering RNA significantly reduced aldosterone-induced collagen accumulation, and aldosterone did not alter the levels of collagen1a1 or matrix metalloproteinase-1 mRNA. The aldosterone-induced TIMP-1 expression was inversely related to matrix metalloproteinase-1 activity. Furthermore, in the animal model, the serum and cardiac levels of TIMP-1 were significantly elevated in the mice that received aldosterone infusion. This elevation was blocked by RU-486 but not by eplerenone, suggesting that the effect was through glucocorticoid receptors. In a long-term aldosterone infusion model, serum TIMP-1 was associated with serum aldosterone level, cardiac structure, and fibrosis. In conclusion, aldosterone induced TIMP-1 expression in vivo and in vitro. This increased TIMP-1 expression resulted in enhanced collagen accumulation via the suppression of matrix metalloproteinase-1 activity.

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“…27,28 Interestingly, aldosterone has been implicated as a mediator of cardiac fibrosis and myocardial necrosis. 29,30 Currently, there are no studies published that have addressed the interaction of the 5-HT 2B receptor and aldosterone in the heart under the pathological condition of hypertension. Therefore, one can speculate that under conditions of hypertension, particularly in the forms of hypertension that are aldosterone dependent, the 5-HT 2B receptor expression may be changed in arteries and also in the heart.…”

Section: Discussionmentioning

confidence: 99%

Upregulation of Arterial Serotonin 1B and 2B Receptors in Deoxycorticosterone Acetate-Salt Hypertension

Banes

Watts

2002

Hypertension

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Abstract-Previous studies have established a role for 5-hydroxytryptamine (5-HT) 2B and 5-HT 1B receptors in mediating enhanced contraction to serotonin (5-HT) in arteries from hypertensive deoxycorticosterone acetate (DOCA)-salt rats.To determine whether the observed increase in responsiveness was due to upregulation of 5-HT receptors, we used Western analysis to measure 5-HT 1B and 5-HT 2B receptor protein density. In endothelium-denuded aortas from hypertensive DOCA-salt rats (mean systolic blood pressure 192Ϯ6 mm Hg), 5-HT 1B and 5-HT 2B receptor proteins were upregulated Ϸ2-fold compared with the response in the aortas of sham-operated control rats (mean systolic blood pressure 119Ϯ2 mm Hg). Contraction to 5-HT 2B receptor agonists was also enhanced in arteries from Wistar-Furth rats given DOCA and salt. This strain is relatively resistant to the hypertensive effects of DOCA and salt treatment. A common factor between the model of DOCA-salt hypertension and the DOCA-salt-treated Wistar-Furth rats is the presence of mineralocorticoids. Therefore, we tested the hypothesis that mineralocorticoids can upregulate 5-HT 1B and 5-HT 2B receptors. Aortas from normal Sprague-Dawley rats were incubated with aldosterone (100 nmol/L) for 8, 12, 24, and 48 hours. The expression of 5-HT 2B and 5-HT 1B receptor proteins was significantly increased (Ϸ2-fold over vehicle treatment) by 8 hours. 5-HT 2B and 5-HT 1B receptors were upregulated by aldosterone in a concentration-dependent manner, and incubation with spironolactone (10 mol/L) blocked this upregulation. These data support the conclusion that the increased expression of 5-HT 1B and 5-HT 2B receptors observed in arteries from DOCA-salt rats may be partially due to mineralocorticoids acting via the mineralocorticoid receptor to modulate gene expression. Recently, in deoxycorticosterone acetate (DOCA)-salt hypertensive rats, 5-HT 2B and 5-HT 1B receptors have been implicated as mediators of 5-HT contractile hyperresponsiveness. 3-6 5-HT 2B and 5-HT 1B receptors do not appear to be involved in mediating contraction to 5-HT under conditions of normal blood pressure. The 5-HT 2B receptor has also been implicated as a mediator of 5-HT-induced contraction in the mesenteric arteries of Wistar and Wistar-Furth rats, which undergo the DOCA-salt protocol. 7 Interestingly, the WistarFurth rat is relatively resistant to the hypertensive effects of mineralocorticoids. 8 -10 This is important to note because although the Wistar-Furth DOCA-salt-treated rats do not obtain the same magnitude of change in blood pressure as do the Wistar DOCA-salt-treated rats, arteries from both of these rats show an increase in response to the 5-HT 2B receptor agonist BW723C86. 7 These previous studies, from the Wistar-Furth as well as the Sprague-Dawley DOCA-salttreated rats, have demonstrated a functional upregulation of the 5-HT 2B receptors. However, none of these studies has addressed the issue of changes in the levels of 5-HT receptor proteins. We speculated that the change in contractility to ...

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Influence of aldosterone on collagen synthesis and proliferation of rat cardiac fibroblasts

Cited by 39 publications

References 52 publications

Salt-Sensitive Blood Pressure in Mice With Increased Expression of Aldosterone Synthase

Salt-Sensitive Blood Pressure in Mice With Increased Expression of Aldosterone Synthase

Aldosterone Induces Tissue Inhibitor of Metalloproteinases-1 Expression and Further Contributes to Collagen Accumulation

Upregulation of Arterial Serotonin 1B and 2B Receptors in Deoxycorticosterone Acetate-Salt Hypertension

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