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Mineralocorticoid Receptors in the Pathophysiology of Vascular Inflammation and Atherosclerosis.

Moss ME, Jaffe IZ - Front Endocrinol (Lausanne) (2015)

Bottom Line: Atherosclerosis is a chronic inflammatory disease of the vasculature that causes significant morbidity and mortality from myocardial infarction, stroke, and peripheral vascular disease.This review summarizes recent advances in our understanding of the role of aldosterone and the MR in the pathogenesis of vascular inflammation and atherosclerosis as it proceeds from risk factor-induced endothelial dysfunction and inflammation to plaque formation, progression, and ultimately rupture with thrombosis, the cause of acute ischemia.A greater understanding of the mechanisms by which the MR promotes atherosclerosis has substantial potential to identify novel treatment targets to improve cardiovascular health and decrease mortality.

View Article: PubMed Central - PubMed

Affiliation: Tufts Medical Center, Molecular Cardiology Research Institute , Boston, MA , USA ; Sackler School of Graduate Biomedical Sciences, Tufts University School of Medicine , Boston, MA , USA.

ABSTRACT
Atherosclerosis is a chronic inflammatory disease of the vasculature that causes significant morbidity and mortality from myocardial infarction, stroke, and peripheral vascular disease. Landmark clinical trials revealed that mineralocorticoid receptor (MR) antagonists improve outcomes in cardiovascular patients. Conversely, enhanced MR activation by the hormone aldosterone is associated with increased risk of MI, stroke, and cardiovascular death. This review summarizes recent advances in our understanding of the role of aldosterone and the MR in the pathogenesis of vascular inflammation and atherosclerosis as it proceeds from risk factor-induced endothelial dysfunction and inflammation to plaque formation, progression, and ultimately rupture with thrombosis, the cause of acute ischemia. The role of the MR in converting cardiac risk factors into endothelial dysfunction, in enhancing leukocyte adhesion and infiltration into the vasculature, in promoting systemic inflammation and vascular oxidative stress, and in plaque destabilization and thrombosis are discussed. A greater understanding of the mechanisms by which the MR promotes atherosclerosis has substantial potential to identify novel treatment targets to improve cardiovascular health and decrease mortality.

No MeSH data available.


Related in: MedlinePlus

Mineralocorticoid receptor contributes to vascular inflammation by activation of NFκB. (A) In whole aorta samples, Aldo acting through the MR upregulates the expression of NFκB precursor subunit p105 and downregulates the NFκB inhibitor IκB, promoting transcription of cytokines IL-6, IL-1β, and TNFα. (B) In ECs, inhibition of the MR with eplerenone attenuates expression of NFκB targets ICAM-1, VCAM, and P-selectin (triangles). In rat mesangial cells, regulation of NFκB by the MR was mediated by SGK-1 inhibition of IκB. (C) Aldo exerts both genomic and non-genomic effects on NFκB target genes in SMCs.
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Figure 2: Mineralocorticoid receptor contributes to vascular inflammation by activation of NFκB. (A) In whole aorta samples, Aldo acting through the MR upregulates the expression of NFκB precursor subunit p105 and downregulates the NFκB inhibitor IκB, promoting transcription of cytokines IL-6, IL-1β, and TNFα. (B) In ECs, inhibition of the MR with eplerenone attenuates expression of NFκB targets ICAM-1, VCAM, and P-selectin (triangles). In rat mesangial cells, regulation of NFκB by the MR was mediated by SGK-1 inhibition of IκB. (C) Aldo exerts both genomic and non-genomic effects on NFκB target genes in SMCs.

Mentions: One mechanism by which Aldo and the MR promote inflammation is by activation of the nuclear factor (NF)κB transcription factor, a critical regulator of cytokine and inflammatory gene expression [reviewed in Ref. (29)]. In primary cultured rat renal collecting duct cells, Aldo-induced NFκB activity and transcription of pro-inflammatory cytokines by a mechanism that required the classical MR genomic target, serum and glucocorticoid regulated kinase-1 [SGK-1 (30)]. In the vasculature of spontaneously hypertensive rats, expression of inflammatory markers IL-1β and IL-6 and the NFκB subunit p105 were increased and the NFκB inhibitor IκB was decreased compared to normotensive rats. The upregulation of NFκB and inflammatory markers was reversed by eplerenone but not by triple antihypertensive therapy, suggesting that the inflammation was due to MR activity rather than simply hypertension (31). Additionally, Aldo treatment of rat vascular SMCs induced NFκB translocation to the nucleus resulting in dose-dependent increases in cyclooxygenase-2 (COX-2) protein abundance and IL-6 mRNA transcripts. IL-6 and COX-2 levels decreased with the addition of inhibitors of the MR or of NFκB, confirming that SMC–MR activation by Aldo promotes inflammatory gene expression by NFκB activation. Aldo may also contribute to SMC inflammatory gene expression through a non-genomic mechanism involving activation of the MAP-kinase/ERK pathway (32). Altogether, these studies demonstrate a role for Aldo and the MR in the development of systemic and vascular inflammation through the downstream actions of NFκB (Figure 2).


Mineralocorticoid Receptors in the Pathophysiology of Vascular Inflammation and Atherosclerosis.

Moss ME, Jaffe IZ - Front Endocrinol (Lausanne) (2015)

Mineralocorticoid receptor contributes to vascular inflammation by activation of NFκB. (A) In whole aorta samples, Aldo acting through the MR upregulates the expression of NFκB precursor subunit p105 and downregulates the NFκB inhibitor IκB, promoting transcription of cytokines IL-6, IL-1β, and TNFα. (B) In ECs, inhibition of the MR with eplerenone attenuates expression of NFκB targets ICAM-1, VCAM, and P-selectin (triangles). In rat mesangial cells, regulation of NFκB by the MR was mediated by SGK-1 inhibition of IκB. (C) Aldo exerts both genomic and non-genomic effects on NFκB target genes in SMCs.
© Copyright Policy
Related In: Results  -  Collection

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Figure 2: Mineralocorticoid receptor contributes to vascular inflammation by activation of NFκB. (A) In whole aorta samples, Aldo acting through the MR upregulates the expression of NFκB precursor subunit p105 and downregulates the NFκB inhibitor IκB, promoting transcription of cytokines IL-6, IL-1β, and TNFα. (B) In ECs, inhibition of the MR with eplerenone attenuates expression of NFκB targets ICAM-1, VCAM, and P-selectin (triangles). In rat mesangial cells, regulation of NFκB by the MR was mediated by SGK-1 inhibition of IκB. (C) Aldo exerts both genomic and non-genomic effects on NFκB target genes in SMCs.
Mentions: One mechanism by which Aldo and the MR promote inflammation is by activation of the nuclear factor (NF)κB transcription factor, a critical regulator of cytokine and inflammatory gene expression [reviewed in Ref. (29)]. In primary cultured rat renal collecting duct cells, Aldo-induced NFκB activity and transcription of pro-inflammatory cytokines by a mechanism that required the classical MR genomic target, serum and glucocorticoid regulated kinase-1 [SGK-1 (30)]. In the vasculature of spontaneously hypertensive rats, expression of inflammatory markers IL-1β and IL-6 and the NFκB subunit p105 were increased and the NFκB inhibitor IκB was decreased compared to normotensive rats. The upregulation of NFκB and inflammatory markers was reversed by eplerenone but not by triple antihypertensive therapy, suggesting that the inflammation was due to MR activity rather than simply hypertension (31). Additionally, Aldo treatment of rat vascular SMCs induced NFκB translocation to the nucleus resulting in dose-dependent increases in cyclooxygenase-2 (COX-2) protein abundance and IL-6 mRNA transcripts. IL-6 and COX-2 levels decreased with the addition of inhibitors of the MR or of NFκB, confirming that SMC–MR activation by Aldo promotes inflammatory gene expression by NFκB activation. Aldo may also contribute to SMC inflammatory gene expression through a non-genomic mechanism involving activation of the MAP-kinase/ERK pathway (32). Altogether, these studies demonstrate a role for Aldo and the MR in the development of systemic and vascular inflammation through the downstream actions of NFκB (Figure 2).

Bottom Line: Atherosclerosis is a chronic inflammatory disease of the vasculature that causes significant morbidity and mortality from myocardial infarction, stroke, and peripheral vascular disease.This review summarizes recent advances in our understanding of the role of aldosterone and the MR in the pathogenesis of vascular inflammation and atherosclerosis as it proceeds from risk factor-induced endothelial dysfunction and inflammation to plaque formation, progression, and ultimately rupture with thrombosis, the cause of acute ischemia.A greater understanding of the mechanisms by which the MR promotes atherosclerosis has substantial potential to identify novel treatment targets to improve cardiovascular health and decrease mortality.

View Article: PubMed Central - PubMed

Affiliation: Tufts Medical Center, Molecular Cardiology Research Institute , Boston, MA , USA ; Sackler School of Graduate Biomedical Sciences, Tufts University School of Medicine , Boston, MA , USA.

ABSTRACT
Atherosclerosis is a chronic inflammatory disease of the vasculature that causes significant morbidity and mortality from myocardial infarction, stroke, and peripheral vascular disease. Landmark clinical trials revealed that mineralocorticoid receptor (MR) antagonists improve outcomes in cardiovascular patients. Conversely, enhanced MR activation by the hormone aldosterone is associated with increased risk of MI, stroke, and cardiovascular death. This review summarizes recent advances in our understanding of the role of aldosterone and the MR in the pathogenesis of vascular inflammation and atherosclerosis as it proceeds from risk factor-induced endothelial dysfunction and inflammation to plaque formation, progression, and ultimately rupture with thrombosis, the cause of acute ischemia. The role of the MR in converting cardiac risk factors into endothelial dysfunction, in enhancing leukocyte adhesion and infiltration into the vasculature, in promoting systemic inflammation and vascular oxidative stress, and in plaque destabilization and thrombosis are discussed. A greater understanding of the mechanisms by which the MR promotes atherosclerosis has substantial potential to identify novel treatment targets to improve cardiovascular health and decrease mortality.

No MeSH data available.


Related in: MedlinePlus