Mineralocorticoid receptor blockade improves diastolic function independent of blood pressure reduction in a transgenic model of RAAS overexpression

Habibi, Javad; DeMarco, Vincent G.; Ma, Lixin; Pulakat, Lakshmi; Rainey, William E.; Whaley‐Connell, Adam; Sowers, James R.

doi:10.1152/ajpheart.01000.2010

Cited by 59 publications

(50 citation statements)

References 48 publications

(137 reference statements)

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“…29 However, the clinical evidence supporting a role of aldosterone and MR activation in the development of LV diastolic dysfunction is weak and mostly suggested by findings of studies conducted with MR antagonists in patients with heart failure and preserved ejection fraction or hypertensive patients with diastolic dysfunction. Mottram et al 15 reported beneficial effects of low-dose spironolactone on myocardial relaxation in 30 treated hypertensive patients with exertional dyspnea and abnormal LV filling patterns.…”

Section: Discussionmentioning

confidence: 99%

Plasma Aldosterone and Left Ventricular Diastolic Function in Treatment-Naïve Patients With Hypertension

et al. 2015

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Diastolic heart failure is detected with increasing frequency in patients with hypertension 1 and is anticipated by changes in left ventricular (LV) filling properties that reflect stiffening of the ventricular wall. These changes in diastolic function can occur even in the absence of hypertension-related LV hypertrophy and are associated with increased hospitalization rate and mortality.2 Therefore, identification of early LV diastolic abnormalities is critical in patients with high blood pressure to prevent subsequent cardiac functional deterioration heralding cardiac insufficiency.3 Conventional echocardiographic techniques cannot detect early changes of diastolic function in a relevant proportion of patients, 4 but pulsed tissue-Doppler imaging (TDI) with measurement of myocardial velocities at several segments of the LV wall permits more sensitive 5 and reproducible 6 detection of diastolic dysfunction. In addition to an increased blood pressure-related cardiac workload, other factors could contribute to the development of structural and functional abnormalities of the heart in patients with hypertension. Evidence obtained in experimental animal studies indicates that inappropriately elevated aldosterone levels and activation of mineralocorticoid receptors (MR) induce profibrotic and hypertrophic responses in the heart. 7-10 Also, studies conducted in patients with primary aldosteronism have consistently reported abnormal LV diastolic properties in association to excess LV hypertrophy in comparison with matched patients with primary hypertension.11,12 However, results of studies that examined the possible contribution of plasma aldosterone levels to LV diastolic dysfunction in primary hypertension were inconsistent 13,14 and also studies that investigated the effects of MR antagonists on LV diastolic function and clinical outcomes in patients with heart failure and preserved ejection fraction reported controversial results. [15][16][17][18] Inconsistencies could be attributed to the use of conventional echocardiography in most of these studies and, most important, to possible interference of drugs used to treat hypertension or heart failure. 19 The aim of this study was, Abstract-Aldosterone has hypertrophic and profibrotic effects on the heart. The relationship between plasma aldosterone levels and left ventricular diastolic function in hypertension, however, is unclear. The aim of this study was to examine this relationship in treatment-naïve hypertensive patients free of comorbidities that could affect left ventricular diastolic filling properties. In 115 patients with primary hypertension who were eating a standard diet and 100 matched normotensive controls, we measured plasma aldosterone and active renin levels and performed both conventional echocardiography and tissue-Doppler imaging for assessment of left ventricular diastolic function. Left ventricular hypertrophy was found in 21% of hypertensive patients, and diastolic dysfunction was detected in 20% by conventional echocardiography and in 58% by ...

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Section: Discussionmentioning

confidence: 99%

Plasma Aldosterone and Left Ventricular Diastolic Function in Treatment-Naïve Patients With Hypertension

et al. 2015

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“…Restraint conditioning was initiated before blood pressure measurements were performed as previously described [14,30]. SBP was measured in triplicate on separate occasions throughout the day using the tail-cuff method (Harvard Systems, Student Oscillometric Recorder) prior to initiation of treatment and on days 19 or 20 and prior to sacrifice at 21 days.…”

Section: Methodsmentioning

confidence: 99%

“…SBP was measured in triplicate on separate occasions throughout the day using the tail-cuff method (Harvard Systems, Student Oscillometric Recorder) prior to initiation of treatment and on days 19 or 20 and prior to sacrifice at 21 days. Urine albumin and creatinine were determined as previously described [14,30]. …”

Section: Methodsmentioning

confidence: 99%

“…Four micrometers of paraffin-embedded sections of kidney were deparaffinized in CitriSolv, rehydrated in ethanol series and Hepes buffer [30,31]. Epitopes were retrieved (antigen retrieval) in citrate buffer pH 6 for 25 min at 95°C.…”

Section: Methodsmentioning

confidence: 99%

“…We further posited that this improvement would be associated with reductions in S6K1 phosphorylation (p)/activation and oxidative stress. To evaluate the blood pressure-independent effects of MR antagonism on PTC integrity and proteinuria, we compared a very low, non-pressure-lowering dose of spironolactone (Sp) [14,29] with that of a conventional pressure-lowering dose [30]. …”

Section: Introductionmentioning

confidence: 99%

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Mineralocorticoid Receptor-Dependent Proximal Tubule Injury Is Mediated by a Redox-Sensitive mTOR/S6K1 Pathway

Whaley‐Connell¹,

Habibi²,

Nistala³

et al. 2011

Am J Nephrol

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Background/Aims: The mammalian target of rapamycin (mTOR) is a serine kinase that regulates phosphorylation (p) of its target ribosomal S6 kinase (S6K1), whose activation can lead to glomerular and proximal tubular cell (PTC) injury and associated proteinuria. Increased mTOR/S6K1 signaling regulates signaling pathways that target fibrosis through adherens junctions. Recent data indicate aldosterone signaling through the mineralocorticoid receptor (MR) can activate the mTOR pathway. Further, antagonism of the MR has beneficial effects on proteinuria that occur independent of hemodynamics. Methods: Accordingly, hypertensive transgenic TG(mRen2)27 (Ren2) rats, with elevated serum aldosterone and proteinuria, and age-matched Sprague-Dawley rats were treated with either a low dose (1 mg/kg/day) or a conventional dose (30 mg/kg/day) of spironolactone (MR antagonist) or placebo for 3 weeks. Results: Ren2 rats displayed increases in urine levels of the PTC brush border lysosomal enzyme N-acetyl-β-aminoglycosidase (β-NAG) in conjunction with reductions in PTC megalin, the apical membrane adherens protein T-cadherin and basolateral α-(E)-catenin, and fibrosis. In concert with these abnormalities, Ren2 renal cortical tissue also displayed increased Ser2448 (p)/activation of mTOR and Thr389 (p)-S6K1 and increased 3-nitrotyrosine (3-NT) content, a marker for peroxynitrite. Low-dose spironolactone had no effect on blood pressure but decreased proteinuria and β-NAG comparable to a conventional dose of this MR antagonist. Both doses of spironolactone attenuated ultrastructural maladaptive alterations and led to comparable reductions in (p)-mTOR/(p)-S6K1, 3-NT, fibrosis, and increased expression of α-(E)-catenin, T- and N-cadherin. Conclusions: Thereby, MR antagonism improves proximal tubule integrity by targeting mTOR/S6K1 signaling and redox status independent of changes in blood pressure.

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Antiarrhythmic Properties of Non-Antiarrhythmic Drugs in Atrial Fibrillation: Upstream Therapy

Scridon

Martínez‐Rubio

2020

Antiarrhythmic Drugs

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Mineralocorticoid receptor blockade improves diastolic function independent of blood pressure reduction in a transgenic model of RAAS overexpression

Cited by 59 publications

References 48 publications

Plasma Aldosterone and Left Ventricular Diastolic Function in Treatment-Naïve Patients With Hypertension

Plasma Aldosterone and Left Ventricular Diastolic Function in Treatment-Naïve Patients With Hypertension

Mineralocorticoid Receptor-Dependent Proximal Tubule Injury Is Mediated by a Redox-Sensitive mTOR/S6K1 Pathway

Antiarrhythmic Properties of Non-Antiarrhythmic Drugs in Atrial Fibrillation: Upstream Therapy

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