Mineralocorticoid Receptor Antagonists in the Management of Heart Failure and Resistant Hypertension

Flatt, David; Brown, Mary Jane; Mizeracki, Adam; King, Bryan J.; Weber, Karl T.

doi:10.1001/jamacardio.2016.1878

Cited by 14 publications

(7 citation statements)

References 77 publications

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“…Mineralocorticoid receptor (MR) is a classic nuclear receptor and its antagonists have been used to treat patients with heart failure or resistant hypertension . MR in ECs has been shown to play important roles in cardiovascular homeostasis and pathogenesis .…”

Section: Introductionmentioning

confidence: 99%

Mineralocorticoid receptor negatively regulates angiogenesis through repression of STAT3 activity in endothelial cells

Zheng

Liu

Zhang

et al. 2019

The Journal of Pathology

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The mineralocorticoid receptor (MR) plays important roles in cardiovascular pathogenesis. The function of MR in angiogenesis is still controversial. This study aimed to explore the role of endothelial MR in angiogenesis and to delineate the underlying mechanism. Endothelial-hematopoietic MR knockout (EMRKO) mice were generated and subjected to hindlimb ischemia and injection of melanoma cells. Laser Doppler measurements showed that EMRKO mice had improved blood flow recovery and increased vessel density in ischemic limbs. In addition, EMRKO accelerated growth and increased the vessel density of tumors. Matrigel implantation, aortic ring assays, and tube formation assays demonstrated that MRKO endothelial cells (ECs) manifested increased angiogenic potential. MRKO ECs also displayed increased migration ability and proliferation. MRKO and MR knockdown both upregulated gene expression, protein level, and phosphorylation of signal transducer and activator of transcription 3 (STAT3). Stattic, a selective STAT3 inhibitor, attenuated the effects of MRKO on tube formation, migration, and proliferation of ECs. At the molecular level, MR interacted with CCAAT enhancer-binding protein beta (C/EBP) to suppress the transcription of STAT3. Furthermore, interactions between MR and STAT3 blocked the phosphorylation of STAT3.Finally, stattic abolished the pro-angiogenic phenotype of EMRKO mice. Taken together, endothelial MR is a negative regulator of angiogenesis, likely in a ligand-independent manner. Mechanistically, MR downregulates STAT3 that mediates the impacts of MR deficiency on the angiogenic activity of ECs and angiogenesis. Targeting endothelial MR may be a potential pro-angiogenic strategy for ischemic diseases.

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Section: Introductionmentioning

confidence: 99%

Mineralocorticoid receptor negatively regulates angiogenesis through repression of STAT3 activity in endothelial cells

Zheng

Liu

Zhang

et al. 2019

The Journal of Pathology

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“…Indeed, epidemiological studies of cardiovascular diseases in men and women as well as in experimental animal models show substantial sexual dimorphism in the incidence and prevalence of arterial hypertension [4,5,6,7]. The renin–angiotensin–aldosterone system and, by extension, the mineralocorticoid receptor (MR) signaling pathway is an important contributor to the emergence of early arterial hypertension and heart failure, with clinical studies demonstrating the beneficial impact of the use of anti-mineralocorticoid drugs [8,9,10]. Moreover, evidence supports the central role of the kidney in the control of blood pressure via the regulation of sodium homeostasis and glucocorticoid metabolism [11,12].…”

Section: Introductionmentioning

confidence: 99%

Sex-Specificity of Mineralocorticoid Target Gene Expression during Renal Development, and Long-Term Consequences

Dumeige

Storey

Decourtye

et al. 2017

IJMS

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Sex differences have been identified in various biological processes, including hypertension. The mineralocorticoid signaling pathway is an important contributor to early arterial hypertension, however its sex-specific expression has been scarcely studied, particularly with respect to the kidney. Basal systolic blood pressure (SBP) and heart rate (HR) were measured in adult male and female mice. Renal gene expression studies of major players of mineralocorticoid signaling were performed at different developmental stages in male and female mice using reverse transcription quantitative PCR (RT-qPCR), and were compared to those of the same genes in the lung, another mineralocorticoid epithelial target tissue that regulates ion exchange and electrolyte balance. The role of sex hormones in the regulation of these genes was also investigated in differentiated KC3AC1 renal cells. Additionally, renal expression of the 11 β-hydroxysteroid dehydrogenase type 2 (11βHSD2) protein, a regulator of mineralocorticoid specificity, was measured by immunoblotting and its activity was indirectly assessed in the plasma using liquid-chromatography coupled to mass spectrometry in tandem (LC-MSMS) method. SBP and HR were found to be significantly lower in females compared to males. This was accompanied by a sex- and tissue-specific expression profile throughout renal development of the mineralocorticoid target genes serum and glucocorticoid-regulated kinase 1 (Sgk1) and glucocorticoid-induced leucine zipper protein (Gilz), together with Hsd11b2, Finally, the implication of sex hormones in this sex-specific expression profile was demonstrated in vitro, most notably for Gilz mRNA expression. We demonstrate a tissue-specific, sex-dependent and developmentally-regulated pattern of expression of the mineralocorticoid pathway that could have important implications in physiology and pathology.

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“…Additional studies are warranted to validate the importance of measuring both plasma aldosterone and ANP in the setting of treated HTN. Further investigations are also warranted to define whether antagonizing aldosterone 30 and/or compensating for the relative ANP deficit 31,32 may be effective strategies for the prevention and treatment of HTN.…”

Section: Discussionmentioning

confidence: 99%

Aldosterone, Hypertension, and Antihypertensive Therapy: Insights From a General Population

Cannone

Buglioni

Sangaralingham

et al. 2018

Mayo Clinic Proceedings

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In this randomly selected general population cohort, aldosterone levels were higher in individuals with HTN compared with normotensive participants. Aldosterone levels increased with anti-HTN medication use. These findings also suggest a relative ANP deficiency with increasing aldosterone levels and anti-HTN drug use. These studies have pathophysiologic and therapeutic implications for targeting aldosterone in the clinical treatment of HTN.

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Mineralocorticoid Receptor Antagonists in the Management of Heart Failure and Resistant Hypertension

Abstract: Mineralocorticoid receptor antagonists are a valuable addition to the practice of medicine. Their judicious use in patients with HF or RHT can improve treatment of these patients.

Cited by 14 publications

References 77 publications

Mineralocorticoid receptor negatively regulates angiogenesis through repression of STAT3 activity in endothelial cells

Mineralocorticoid receptor negatively regulates angiogenesis through repression of STAT3 activity in endothelial cells

Sex-Specificity of Mineralocorticoid Target Gene Expression during Renal Development, and Long-Term Consequences

Aldosterone, Hypertension, and Antihypertensive Therapy: Insights From a General Population

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