Steroidogenesis vs. steroid uptake in the heart: do corticosteroids mediate effects via cardiac mineralocorticoid receptors?

Chai, Wenxia; Hofland, Johannes; Jansen, Pieter; Garrelds, Ingrid M.; Vries, René de; Bogaerdt, Antoon J. van den; Feelders, Richard A; Jong, Frank H. de; Danser, A.H. Jan

doi:10.1097/hjh.0b013e328335c381

Cited by 39 publications

(40 citation statements)

References 38 publications

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“…Moreover, our recent study demonstrated that there is a transient decrease in serum potassium level during ischemic attacks of acute coronary syndrome, which is at least partially mediated through the activation of the aldosterone cascade (Sekiyama et al 2013). Although these clinical findings provide evidence for local cardiac aldosterone synthesis/actions, this issue remains very controversial, and in fact, some reports have offered negative findings regarding the question of local aldosterone synthesis in the heart (Gomez-Sanchez et al 2004, Fiebeler et al 2005, Chai et al 2010. In any case, the results of the current study confirm the speculation that, while aldosterone generally has little effect on the cardiovascular system under baseline normal conditions (Oliver et al 1975), an elevated local/systemic aldosterone level (even within the physiological range, from the low-normal range to the high-normal or just above the normal range, which does not generally exceed a pharmacological dose of over 10 K8 mol/l) in rapid response to severe cardiac conditions exerts substantial effects on cardiac function, which initially act in a cardioprotective manner.…”

Section: Discussionmentioning

confidence: 97%

Preconditioning actions of aldosterone through p38 signaling modulation in isolated rat hearts

Yoshino¹,

Nagoshi²,

Anzawa³

et al. 2014

Journal of Endocrinology

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Although persistent excessive actions of aldosterone have unfavorable effects on the cardiovascular system, primarily via mineralocorticoid receptor (MR)-dependent pathways, the pathophysiological significance of aldosterone cascade activation in heart diseases has not yet been fully clarified. We herein examined the effects of short-term aldosterone stimulation at a physiological dose on cardiac function during ischemia-reperfusion injury (IRI). In order to study the effects of aldosterone preconditioning, male Wistar rat Langendorff hearts were perfused with 10 K9 mol/l of aldosterone for 10 min before ischemia, and the response to IRI was assessed. Although aldosterone did not affect the baseline hemodynamic parameters, preconditioning actions of aldosterone significantly improved the recovery in left ventricular contractility and left ventricular end-diastolic pressure associated with a reduced activity of creatine phosphokinase released into the perfusate after ischemia-reperfusion. Notably, the MR inhibitor eplerenone did not abrogate these beneficial effects. Biochemical analyses revealed that p38MAPK phosphorylation was significantly increased during aldosterone preconditioning before ischemia, whereas its phosphorylation was substantially attenuated during sustained ischemiareperfusion, compared with the results for in the non-preconditioned control hearts. This dual regulation of p38MAPK was not affected by eplerenone. The phosphorylation levels of other MAPKs were not altered by aldosterone preconditioning. In conclusion, the temporal induction of the aldosterone cascade, at a physiological dose, has favorable effects on cardiac functional recovery and injury following ischemia-reperfusion in a MR-independent manner. Phasic dynamism of p38MAPK activation may play a key role in the physiological compensatory pathway of aldosterone under severe cardiac pathological conditions.

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Section: Discussionmentioning

confidence: 97%

Preconditioning actions of aldosterone through p38 signaling modulation in isolated rat hearts

Yoshino¹,

Nagoshi²,

Anzawa³

et al. 2014

Journal of Endocrinology

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“…transcriptase reaction, and quantitative PCR (qPCR) were performed as described previously (Chai et al 2010). The qPCR was performed in a 12 .…”

Section: Measurement Of Steroid Hormone Concentrationsmentioning

confidence: 99%

“…The qPCR was performed in a 12 . 5 ml volume for the housekeeping gene HPRT1 and steroidogenic enzymes STAR, CYP11A1, HSD3B2, CYP17A1, CYP21A2, and CYP11B1 (primer sequences have been reported in Chai et al (2010)). After 72 h, vehicle-controlled mRNA expression levels of steroidogenic enzymes were calculated relative to those of the housekeeping gene HPRT1 using the DCt method.…”

Section: Measurement Of Steroid Hormone Concentrationsmentioning

confidence: 99%

Fluconazole inhibits human adrenocortical steroidogenesis in vitro

Pas¹,

Hofland²,

Hofland³

et al. 2012

Journal of Endocrinology

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The antifungal agent ketoconazole is often used to suppress cortisol production in patients with Cushing's syndrome (CS). However, ketoconazole has serious side effects and is hepatotoxic. Here, the in vitro effects of ketoconazole and fluconazole, which might be less toxic, on human adrenocortical steroidogenesis were compared. The effects on steroidogenesis were examined in primary cultures of nine human adrenocortical tissues and two human adrenocortical carcinoma cell lines. Moreover, the effects on mRNA expression levels of steroidogenic enzymes and cell growth were assessed. Ketoconazole significantly inhibited 11-deoxycortisol (H295R cells; maximum inhibition 99%; EC 50 0 . 73 mM) and cortisol production (HAC15 cells; 81%; EC 50 0 . 26 mM and primary cultures (mean EC 50 0 . 75 mM)). In cultures of normal adrenal cells, ketoconazole increased pregnenolone, progesterone, and deoxycorticosterone levels, while concentrations of 17-hydroxypregnenolone, 17-hydroxyprogesterone, 11-deoxycortisol, DHEA, and androstenedione decreased. Fluconazole also inhibited 11-deoxycortisol production in H295R cells (47%; only at 1 mM) and cortisol production in HAC15 cells (maximum inhibition 55%; EC 50 35 mM) and primary cultures (mean EC 50 67 . 7 mM). In the cultures of normal adrenals, fluconazole suppressed corticosterone, 17-hydroxypregnenolone, and androstenedione levels, whereas concentrations of progesterone, deoxycorticosterone, and 11-deoxycortisol increased. Fluconazole (1 mM) slightly increased STAR mRNA expression in both cell lines. Neither compound affected mRNA levels of other steroidogenic enzymes or cell number. In conclusion, by inhibiting 11b-hydroxylase and 17-hydroxylase activity, pharmacological concentrations of fluconazole dose dependently inhibit cortisol production in human adrenocortical cells in vitro. Although fluconazole seems less potent than ketoconazole, it might become an alternative for ketoconazole to control hypercortisolism in CS. Furthermore, patients receiving fluconazole because of mycosis might be at risk for developing adrenocortical insufficiency.

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“…It also stimulates aldosterone by aldosterone synthase (CYP11B2) synthesis, thereby increasing the release of aldosterone, which promotes fluid retention and cardiac fibrosis. 11 Previous studies suggested a role for specific genetic variants in genes encoding components of the RAAS pathway in modulation of the severity of LVH in patients with HCM. [12][13][14] In particular, two studies investigated five candidate polymorphisms within these genes in HCM patients with an identified HCM-causing mutation.…”

Section: Introductionmentioning

confidence: 99%

The role of renin–angiotensin–aldosterone system polymorphisms in phenotypic expression of MYBPC3-related hypertrophic cardiomyopathy

et al. 2012

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The phenotypic variability of hypertrophic cardiomyopathy (HCM) in patients with identical pathogenic mutations suggests additional modifiers. In view of the regulatory role in cardiac function, blood pressure, and electrolyte homeostasis, polymorphisms in the renin-angiotensin-aldosterone system (RAAS) are candidates for modifying phenotypic expression. In order to investigate whether RAAS polymorphisms modulate HCM phenotype, we selected a large cohort of carriers of one of the three functionally equivalent truncating mutations in the MYBPC3 gene. Family-based association analysis was performed to analyze the effects of five candidate RAAS polymorphisms (ACE, rs4646994; AGTR1, rs5186; CMA, rs1800875; AGT, rs699; CYP11B2, rs1799998) in 368 subjects carrying one of the three mutations in the MYBPC3 gene. Interventricular septum (IVS) thickness and Wigle score were assessed by 2D-echocardiography. SNPs in the RAAS system were analyzed separately and combined as a pro-left ventricular hypertrophy (LVH) score for effects on the HCM phenotype. Analyzing the five polymorphisms separately for effects on IVS thickness and Wigle score detected two modest associations. Carriers of the CC genotype in the AGT gene had less pronounced IVS thickness compared with CT and TT genotype carriers. The DD polymorphism in the ACE gene was associated with a high Wigle score (P ¼ 0.01). No association was detected between the pro-LVH score and IVS thickness or Wigle score. In conclusion, in contrast to previous studies, in our large study population of HCM patients with functionally equivalent mutations in the MYBPC3 gene we did not find major effects of genetic variation within the genes of the RAAS system on phenotypic expression of HCM.

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Steroidogenesis vs. steroid uptake in the heart: do corticosteroids mediate effects via cardiac mineralocorticoid receptors?

Abstract: Both cortisol/corticosterone and aldosterone accumulate in the cardiac interstitium. The presence of HSD11B2 and mineralocorticoid receptors/glucocorticoid receptors at cardiac tissue sites allows both steroids to exert their effects via separate mechanisms.

Cited by 39 publications

References 38 publications

Preconditioning actions of aldosterone through p38 signaling modulation in isolated rat hearts

Preconditioning actions of aldosterone through p38 signaling modulation in isolated rat hearts

Fluconazole inhibits human adrenocortical steroidogenesis in vitro

The role of renin–angiotensin–aldosterone system polymorphisms in phenotypic expression of MYBPC3-related hypertrophic cardiomyopathy

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