Vascular Mineralocorticoid Receptor: Evolutionary Mediator of Wound Healing Turned Harmful by Our Modern Lifestyle

Biwer, Lauren A; Wallingford, Mary C.; Jaffe, Iris Z.

doi:10.1093/ajh/hpy158

Cited by 28 publications

(26 citation statements)

References 97 publications

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“…However, modern lifestyle and sedentary behavior associated with an unhealthy diet rich in salt may have turned the aldosterone/MR defense mechanism into a harmful one that contributes to increase in blood pressure, cardiovascular disease, and events in populations with obesity and advanced age. 43 …”

mentioning

confidence: 99%

Aldosterone, Inflammation, Immune System, and Hypertension

Ferreira

Tostes

Paradis

et al. 2020

American Journal of Hypertension

143

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Aldosterone is a mineralocorticoid hormone that controls body fluid and electrolyte balance. Excess aldosterone is associated with cardiovascular and metabolic diseases. Inflammation plays a critical role on vascular damage promoted by aldosterone and aggravates vascular abnormalities, including endothelial dysfunction, vascular remodeling, fibrosis and oxidative stress and other manifestations of end-organ damage, that are associated with hypertension, other forms of cardiovascular disease, and diabetes mellitus and the metabolic syndrome. Over the past few years, many studies have consistently shown that aldosterone activates cells of the innate and adaptive immune systems. Macrophages and T cells accumulate in the kidneys, heart and vasculature in response to aldosterone, and infiltration of immune cells contributes to end-organ damage in cardiovascular and metabolic diseases. Aldosterone activates various subsets of innate immune cells such as dendritic cells and monocytes/macrophages, as well as adaptive immune cells such as T lymphocytes, and, by activation of mineralocorticoid receptors stimulates pro-inflammatory transcription factors and the production of adhesion molecules and inflammatory cytokines and chemokines. This review will briefly highlight some of the studies on the involvement of aldosterone in activation of innate and adaptive immune cells and its impact on the cardiovascular system. Since aldosterone plays a key role in many cardiovascular and metabolic diseases, these data will open up promising perspectives for the identification of novel biomarkers and therapeutic targets for prevention and treatment of diseases associated with increased levels of aldosterone, such as arterial hypertension, obesity, the metabolic syndrome and heart failure.

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mentioning

confidence: 99%

Aldosterone, Inflammation, Immune System, and Hypertension

Ferreira

Tostes

Paradis

et al. 2020

American Journal of Hypertension

143

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“…Blocking mineralocorticoid receptor with spironolactone may have a wide range of therapeutic actions in severe COVID-19 disease Lucas Liaudet 1* and Csaba Szabo 2 The pulmonary renin angiotensin (Ang) system (RAS) comprises two pathways whose balance is important for lung homeostasis. Endothelial ACE generates Ang II, acting on AT1 receptors to promote vasoconstriction and pro-inflammatory effects, whereas epithelial ACE2 cleaves Ang II into Ang1-7, acting on the Mas receptor to exert vasodilatory and anti-inflammatory effects.…”

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confidence: 99%

“…SARS-CoV-2 uses lung ACE2 as its cellular receptor, resulting in ACE2 degradation and ACE/ACE2 imbalance, which could drive Ang II-mediated vascular inflammation and lung injury in severe COVID-19 disease [1]. Furthermore, Ang II induces the release of aldosterone, which can promote further vascular damage via mineralocorticoid receptor (MR) activation [2]. Aldosterone also exerts multiple actions on immune cells, which express the MR [3].…”

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confidence: 99%

Blocking mineralocorticoid receptor with spironolactone may have a wide range of therapeutic actions in severe COVID-19 disease

Liaudet¹,

Szabó

2020

Crit Care

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“…Further, activation of the AT1R by Ang II stimulates the secretion of aldosterone which through its action on AR augments "killer pathway" induced hyper-inflammation by its effect through the Mineralocorticoid Receptor (MR) (Figure 4) Mineralocorticoid Receptor: Angiotensin II induces aldosterone's release from the adrenal cortex, promoting vascular damage via MR activation. 36 Aldosterone also exerts multiple actions on immune cells, which expressMR. 37 Dysregulated RAAS signaling with enhanced aldosterone-mediated MR activation could represent an important link between COVID-19/ACE2 interaction and inflammatory lung injury, suggesting an interesting therapeutic potential for RAAS inhibitors and in particular MR antagonists 38 (Figure 4).…”

Section: Angiotensin-converting Enzyme 2 At1 At2 and Masmentioning

confidence: 99%

The COVID-19 Code – Cracked – WHO can Save The World (?)!

Kuppuswamy¹,

Nagarajan²,

Balasubramaniam³

et al. 2020

IJISRT

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The first step in COVID-19 pathogenesis is the viral spike protein priming by Trans Membrane Peptide Receptor Serine S2 (TMPRSS2). TMPRSS2 promotes viral entry, cell to cell transmission, evasion of host immune response, and Angiotensin-Converting Enzyme 2 (ACE2) downregulation. Androgen through Androgen Receptor (AR) increases TMPRSS2 gene expression. Blocking AR may prevent viral entry and other TMPRSS2 mediated actions. ACE2 acts as an entry point for COVID-19 and as the counter regulator in Renin-Angiotensin-Aldosterone System (RAAS). RAAS maintains homeostasis of blood pressure, salt and water, inflammation, and immune response – through its two arms called “killer” and “protective pathways.” The balance between these two pathways determines life or death in disease states. ACE2 converts Angiotensin II to Angiotensin (1-7), which through Mas receptors mediates antiinflammatory, immune-modulatory, and anti-fibrotic actions. Angiotensin II also acts on Angiotensin type 2 Receptor (AT2R) to produce similar actions, called a "protective pathway." Further, Angiotensin II acts through its primary Angiotensin type 1 Receptor (AT1R), causing inflammatory, cytokine storm, and profibrotic response – called "Killer pathway." In COVID, down-regulated ACE2 leads to unabated Angiotensin II/AT1R – "Killer pathway" – actions producing a vicious cycle of "hyper-inflammatory state," resulting in ALI, ARDS, and death. AT1R activation further stimulates the secretion of aldosterone, which through Mineralocorticoid Receptor (MR), augments AT1R mediated 'killer pathway”. None of the COVID guideline drugs modulate this pathogenic mechanism. We examine the first time in history the scientific rationale for combined AR/AT1R/MR blockade for COVID-19 treatment and prevention.

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Vascular Mineralocorticoid Receptor: Evolutionary Mediator of Wound Healing Turned Harmful by Our Modern Lifestyle

Cited by 28 publications

References 97 publications

Aldosterone, Inflammation, Immune System, and Hypertension

Aldosterone, Inflammation, Immune System, and Hypertension

Blocking mineralocorticoid receptor with spironolactone may have a wide range of therapeutic actions in severe COVID-19 disease

The COVID-19 Code – Cracked – WHO can Save The World (?)!

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