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Role of Aldosterone Excess in Determining Cardiovascular Risk
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Role of Aldosterone Excess in Determining Cardiovascular Risk

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Endocrinology and Metabolism".

Deadline for manuscript submissions: closed (31 May 2022) | Viewed by 18548

Special Issue Editor

Dr. Luigi Petramala

E-Mail Website
Guest Editor
Department of Translational and Precision Medicine, Unit of Secondary Arterial Hypertension, “Sapienza” University of Rome, Viale del Policlinico 155, 00165 Rome, Italy
Interests: hypertension; endothelial dysfunction; ischemic heart disease; arrhythmia; target organ damage; cardiovascular risk factors
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

In recent years, numerous studies have confirmed the prominent role of primary hyperaldosteronism (PA), due to its high frequency among secondary forms of arterial hypertension and to specific deleterious effects on global cardiovascular risk; numerous studies have also evaluated how the excess of aldosterone directly causes important changes in the heart, vascular system, and metabolic balance, favoring arrhythmias, cardiac remodeling, metabolic alterations, increased oxidative stress, and thrombosis.

The purpose of this Special Issue is to highlight the direct role of excess aldosterone in the determination of higher global cardiovascular risk.

Dr. Luigi Petramala
Guest Editor

Manuscript Submission Information

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Keywords

  • primary hyperaldosteronism
  • global cardiovascular risk
  • heart
  • vascular system
  • metabolic alterations
  • oxidative stress
  • thrombosis

Published Papers (6 papers)

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Research

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16 pages, 3257 KiB  
Article
ATP1A1 Mutant in Aldosterone-Producing Adenoma Leads to Cell Proliferation
by Kazuhiro Kobuke, Kenji Oki, Celso E. Gomez-Sanchez, Elise P. Gomez-Sanchez, Kiyotaka Itcho, Haruya Ohno, Gaku Nagano, Yoko Yoshii, Ryuta Baba, Takaya Kodama, Koji Arihiro, Noboru Hattori and Masayasu Yoneda
Int. J. Mol. Sci. 2021, 22(20), 10981; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms222010981 - 12 Oct 2021
Cited by 5 | Viewed by 2591
Abstract
The molecular mechanisms by which ATP1A1 mutation-mediated cell proliferation or tumorigenesis in aldosterone-producing adenomas (APAs) have not been elucidated. First, we investigated whether the APA-associated ATP1A1 L104R mutation stimulated cell proliferation. Second, we aimed to clarify the molecular mechanisms by which the ATP1A1 [...] Read more.
The molecular mechanisms by which ATP1A1 mutation-mediated cell proliferation or tumorigenesis in aldosterone-producing adenomas (APAs) have not been elucidated. First, we investigated whether the APA-associated ATP1A1 L104R mutation stimulated cell proliferation. Second, we aimed to clarify the molecular mechanisms by which the ATP1A1 mutation-mediated cell proliferated. We performed transcriptome analysis in APAs with ATP1A1 mutation. ATP1A1 L104R mutation were modulated in human adrenocortical carcinoma (HAC15) cells (ATP1A1-mutant cells), and we evaluated cell proliferation and molecular signaling events. Transcriptome and immunohistochemical analysis showed that Na/K-ATPase (NKA) expressions in ATP1A1 mutated APA were more abundant than those in non-functioning adrenocortical adenoma or KCNJ5 mutated APAs. The significant increase of number of cells, amount of DNA and S-phase population were shown in ATP1A1-mutant cells. Fluo-4 in ATP1A1-mutant cells were significantly increased. Low concentration of ouabain stimulated cell proliferation in ATP1A1-mutant cells. ATP1A1-mutant cells induced Src phosphorylation, and low concentration of ouabain supplementation showed further Src phosphorylation. We demonstrated that NKAs were highly expressed in ATP1A1 mutant APA, and the mutant stimulated cell proliferation and Src phosphorylation in ATP1A1-mutant cells. NKA stimulations would be a risk factor for the progression and development to an ATP1A1 mutant APA. Full article
(This article belongs to the Special Issue Role of Aldosterone Excess in Determining Cardiovascular Risk)
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16 pages, 3134 KiB  
Article
Aldosterone Negatively Regulates Nrf2 Activity: An Additional Mechanism Contributing to Oxidative Stress and Vascular Dysfunction by Aldosterone
by Daniel Rodrigues, Tiago J. Costa, Josiane F. Silva, José Teles de Oliveira Neto, Juliano V. Alves, Aline G. Fedoce, Rafael Menezes Costa and Rita C. Tostes
Int. J. Mol. Sci. 2021, 22(11), 6154; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22116154 - 07 Jun 2021
Cited by 7 | Viewed by 3004
Abstract
High levels of aldosterone (Aldo) trigger oxidative stress and vascular dysfunction independent of effects on blood pressure. We sought to determine whether Aldo disrupts Nrf2 signaling, the main transcriptional factor involved in antioxidant responses that aggravate cell injury. Thoracic aorta from male C57Bl/6J [...] Read more.
High levels of aldosterone (Aldo) trigger oxidative stress and vascular dysfunction independent of effects on blood pressure. We sought to determine whether Aldo disrupts Nrf2 signaling, the main transcriptional factor involved in antioxidant responses that aggravate cell injury. Thoracic aorta from male C57Bl/6J mice and cultured human endothelial cells (EA.hy926) were stimulated with Aldo (100 nM) in the presence of tiron [reactive oxygen species (ROS) scavenger, eplerenone [mineralocorticoid receptor (MR) antagonist], and L-sulforaphane (SFN; Nrf2 activator). Thoracic aortas were also isolated from mice infused with Aldo (600 μg/kg per day) for 14 days. Aldo decreased endothelium-dependent vasorelaxation and increased ROS generation, effects prevented by tiron and MR blockade. Pharmacological activation of Nrf2 with SFN abrogated Aldo-induced vascular dysfunction and ROS generation. In EA.hy926 cells, Aldo increased ROS generation, which was prevented by eplerenone, tiron, and SFN. At short times, Aldo-induced ROS generation was linked to increased Nrf2 activation. However, after three hours, Aldo decreased the nuclear accumulation of Nrf2. Increased Keap1 protein expression, but not activation of p38 MAPK, was linked to Aldo-induced reduced Nrf2 activity. Arteries from Aldo-infused mice also exhibited decreased nuclear Nrf2 and increased Keap1 expression. Our findings suggest that Aldo reduces vascular Nrf2 transcriptional activity by Keap1-dependent mechanisms, contributing to mineralocorticoid-induced vascular dysfunction. Full article
(This article belongs to the Special Issue Role of Aldosterone Excess in Determining Cardiovascular Risk)
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13 pages, 1980 KiB  
Article
Id2 Represses Aldosterone-Stimulated Cardiac T-Type Calcium Channels Expression
by Jumpei Ito, Tomomi Minemura, Sébastien Wälchli, Tomoaki Niimi, Yoshitaka Fujihara, Shun’ichi Kuroda, Koichi Takimoto and Andrés D. Maturana
Int. J. Mol. Sci. 2021, 22(7), 3561; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22073561 - 30 Mar 2021
Cited by 4 | Viewed by 2565
Abstract
Aldosterone excess is a cardiovascular risk factor. Aldosterone can directly stimulate an electrical remodeling of cardiomyocytes leading to cardiac arrhythmia and hypertrophy. L-type and T-type voltage-gated calcium (Ca2+) channels expression are increased by aldosterone in cardiomyocytes. To further understand the regulation [...] Read more.
Aldosterone excess is a cardiovascular risk factor. Aldosterone can directly stimulate an electrical remodeling of cardiomyocytes leading to cardiac arrhythmia and hypertrophy. L-type and T-type voltage-gated calcium (Ca2+) channels expression are increased by aldosterone in cardiomyocytes. To further understand the regulation of these channels expression, we studied the role of a transcriptional repressor, the inhibitor of differentiation/DNA binding protein 2 (Id2). We found that aldosterone inhibited the expression of Id2 in neonatal rat cardiomyocytes and in the heart of adult mice. When Id2 was overexpressed in cardiomyocytes, we observed a reduction in the spontaneous action potentials rate and an arrest in aldosterone-stimulated rate increase. Accordingly, Id2 siRNA knockdown increased this rate. We also observed that CaV1.2 (L-type Ca2+ channel) or CaV3.1, and CaV3.2 (T-type Ca2+ channels) mRNA expression levels and Ca2+ currents were affected by Id2 presence. These observations were further corroborated in a heart specific Id2- transgenic mice. Taken together, our results suggest that Id2 functions as a transcriptional repressor for L- and T-type Ca2+ channels, particularly CaV3.1, in cardiomyocytes and its expression is controlled by aldosterone. We propose that Id2 might contributes to a protective mechanism in cardiomyocytes preventing the presence of channels associated with a pathological state. Full article
(This article belongs to the Special Issue Role of Aldosterone Excess in Determining Cardiovascular Risk)
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Review

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10 pages, 596 KiB  
Review
Prognostic Role of sST2 in Acute Heart Failure and COVID-19 Infection—A Narrative Review on Pathophysiology and Clinical Prospective
by Luca Marino, Antonio Concistrè, Marianna Suppa, Gioacchino Galardo, Antonello Rosa, Giuliano Bertazzoni, Francesco Pugliese, Claudio Letizia and Luigi Petramala
Int. J. Mol. Sci. 2022, 23(15), 8230; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23158230 - 26 Jul 2022
Cited by 7 | Viewed by 2019
Abstract
The importance of cardiovascular biomarkers in clinical practice increased dramatically in the last years, and the interest extends from the diagnosis purpose to prognostic applications and response to specific treatment. Acute heart failure, ischemic heart failure, and COVID-19 infection represent different clinical settings [...] Read more.
The importance of cardiovascular biomarkers in clinical practice increased dramatically in the last years, and the interest extends from the diagnosis purpose to prognostic applications and response to specific treatment. Acute heart failure, ischemic heart failure, and COVID-19 infection represent different clinical settings that are challenging in terms of the proper prognostic establishment. The aim of the present review is to establish the useful role of sST2, the soluble form of the interleukin-1 receptor superfamily (ST2), physiologically involved in the signaling of interleukin-33 (IL-33)-ST2 axis, in the clinical setting of acute heart failure (HF), ischemic heart disease, and SARS-CoV-2 acute infection. Molecular mechanisms associated with the IL33/ST2 signaling pathways are discussed in view of the clinical usefulness of biomarkers to early diagnosis, evaluation therapy to response, and prediction of adverse outcomes in cardiovascular diseases. Full article
(This article belongs to the Special Issue Role of Aldosterone Excess in Determining Cardiovascular Risk)
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16 pages, 1138 KiB  
Review
Primary Aldosteronism and Resistant Hypertension: A Pathophysiological Insight
by Fabio Bioletto, Martina Bollati, Chiara Lopez, Stefano Arata, Matteo Procopio, Federico Ponzetto, Ezio Ghigo, Mauro Maccario and Mirko Parasiliti-Caprino
Int. J. Mol. Sci. 2022, 23(9), 4803; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23094803 - 27 Apr 2022
Cited by 14 | Viewed by 4775
Abstract
Primary aldosteronism (PA) is a pathological condition characterized by an excessive aldosterone secretion; once thought to be rare, PA is now recognized as the most common cause of secondary hypertension. Its prevalence increases with the severity of hypertension, reaching up to 29.1% in [...] Read more.
Primary aldosteronism (PA) is a pathological condition characterized by an excessive aldosterone secretion; once thought to be rare, PA is now recognized as the most common cause of secondary hypertension. Its prevalence increases with the severity of hypertension, reaching up to 29.1% in patients with resistant hypertension (RH). Both PA and RH are “high-risk phenotypes”, associated with increased cardiovascular morbidity and mortality compared to non-PA and non-RH patients. Aldosterone excess, as occurs in PA, can contribute to the development of a RH phenotype through several mechanisms. First, inappropriate aldosterone levels with respect to the hydro-electrolytic status of the individual can cause salt retention and volume expansion by inducing sodium and water reabsorption in the kidney. Moreover, a growing body of evidence has highlighted the detrimental consequences of “non-classical” effects of aldosterone in several target tissues. Aldosterone-induced vascular remodeling, sympathetic overactivity, insulin resistance, and adipose tissue dysfunction can further contribute to the worsening of arterial hypertension and to the development of drug-resistance. In addition, the pro-oxidative, pro-fibrotic, and pro-inflammatory effects of aldosterone may aggravate end-organ damage, thereby perpetuating a vicious cycle that eventually leads to a more severe hypertensive phenotype. Finally, neither the pathophysiological mechanisms mediating aldosterone-driven blood pressure rise, nor those mediating aldosterone-driven end-organ damage, are specifically blocked by standard first-line anti-hypertensive drugs, which might further account for the drug-resistant phenotype that frequently characterizes PA patients. Full article
(This article belongs to the Special Issue Role of Aldosterone Excess in Determining Cardiovascular Risk)
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14 pages, 1351 KiB  
Review
Atrial Fibrillation and Aortic Ectasia as Complications of Primary Aldosteronism: Focus on Pathophysiological Aspects
by Martina Bollati, Chiara Lopez, Fabio Bioletto, Federico Ponzetto, Ezio Ghigo, Mauro Maccario and Mirko Parasiliti-Caprino
Int. J. Mol. Sci. 2022, 23(4), 2111; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms23042111 - 14 Feb 2022
Cited by 6 | Viewed by 2433
Abstract
Primary aldosteronism (PA) is the most common cause of secondary hypertension. A growing body of evidence has suggested that, beyond its well-known effects on blood pressure and electrolyte balance, aldosterone excess can exert pro-inflammatory, pro-oxidant and pro-fibrotic effects on the kidney, blood vessels [...] Read more.
Primary aldosteronism (PA) is the most common cause of secondary hypertension. A growing body of evidence has suggested that, beyond its well-known effects on blood pressure and electrolyte balance, aldosterone excess can exert pro-inflammatory, pro-oxidant and pro-fibrotic effects on the kidney, blood vessels and heart, leading to potentially harmful pathophysiological consequences. In clinical studies, PA has been associated with an increased risk of cardiovascular, cerebrovascular, renal and metabolic complication compared to essential hypertension, including atrial fibrillation (AF) and aortic ectasia. An increased prevalence of AF in patients with PA has been demonstrated in several clinical studies. Aldosterone excess seems to be involved in the pathogenesis of AF by inducing cardiac structural and electrical remodeling that in turn predisposes to arrhythmogenicity. The association between PA and aortic ectasia is less established, but several studies have demonstrated an effect of aldosterone on aortic stiffness, vascular smooth muscle cells and media composition that, in turn, might lead to an increased risk of aortic dilation and dissection. In this review, we focus on the current evidence regarding the potential role of aldosterone excess in the pathogenesis of AF and aortic ectasia. Full article
(This article belongs to the Special Issue Role of Aldosterone Excess in Determining Cardiovascular Risk)
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