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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

Aldo and MR in vascular inflammation. (1) Aldo induces systemic inflammation in the setting of cardiovascular risk factors. (2) In response to endothelial damage, Aldo acts on EC–MR to induce cytokine and adhesion molecule expression. (3) Cytokines produced by the endothelium and underlying SMCs induce EC adhesion molecule expression and leukocyte recruitment, adhesion, and transmigration. (4) Aldo also acts on EC–MR to induce rearrangement of the actin cytoskeleton, possibly facilitating leukocyte transmigration. (5) Myeloid MR induces ROS production and macrophage activation and polarization to the M1 phenotype. (6) MR induces T cell expression of homing markers and differentiation to the Th17 subset. (7) Aldo activation of neutrophil MR induces MMP-9 production, which may promote atherosclerotic plaque rupture.
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Figure 1: Aldo and MR in vascular inflammation. (1) Aldo induces systemic inflammation in the setting of cardiovascular risk factors. (2) In response to endothelial damage, Aldo acts on EC–MR to induce cytokine and adhesion molecule expression. (3) Cytokines produced by the endothelium and underlying SMCs induce EC adhesion molecule expression and leukocyte recruitment, adhesion, and transmigration. (4) Aldo also acts on EC–MR to induce rearrangement of the actin cytoskeleton, possibly facilitating leukocyte transmigration. (5) Myeloid MR induces ROS production and macrophage activation and polarization to the M1 phenotype. (6) MR induces T cell expression of homing markers and differentiation to the Th17 subset. (7) Aldo activation of neutrophil MR induces MMP-9 production, which may promote atherosclerotic plaque rupture.

Mentions: Atherosclerosis begins with dysfunction of the vascular endothelium. Healthy endothelial cells (ECs) contribute to vasodilation by producing nitric oxide via endothelial nitric oxide synthase (eNOS) activity. Nitric oxide production is impaired early in atherogenesis, and the downstream effects of this can be measured in vivo by tonometry and flow-mediated vasodilation or ex vivo by quantifying achetylcholine-induced vasodilation of arterial rings. Aldo and vascular MR have been recently implicated in the development of endothelial dysfunction in humans with cardiovascular risk factors and in corresponding animal models. Hypertensive African-Americans had impaired endothelial function, as measured by pulse arterial tonography and by ex vivo studies of adipose vessels, which was improved with spironolactone treatment. Conversely, normotensive subjects had impaired endothelial function after Aldo administration, which was also prevented by spironolactone (17). Hypertensive subjects had an associated decrease in arteriolar glucose-6-phosphate dehydrogenase (G6PD) activity compared to non-hypertensives. A potential mechanism is suggested by a prior study demonstrating that Aldo treatment of bovine ECs in vitro and of mice in vivo decreases EC G6PD expression, resulting in excessive production of reactive oxygen species [ROS (18)]. In another study, treatment of diabetics with spironolactone improved coronary flow reserve, as measured by cardiac PET scan, compared to subjects treated with hydrochlorothiazide to achieve the same blood pressure (19). Thus, in patients with risk factors including hypertension and diabetes, endothelial dysfunction appears to be MR dependent (Figure 1).


Mineralocorticoid Receptors in the Pathophysiology of Vascular Inflammation and Atherosclerosis.

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

Aldo and MR in vascular inflammation. (1) Aldo induces systemic inflammation in the setting of cardiovascular risk factors. (2) In response to endothelial damage, Aldo acts on EC–MR to induce cytokine and adhesion molecule expression. (3) Cytokines produced by the endothelium and underlying SMCs induce EC adhesion molecule expression and leukocyte recruitment, adhesion, and transmigration. (4) Aldo also acts on EC–MR to induce rearrangement of the actin cytoskeleton, possibly facilitating leukocyte transmigration. (5) Myeloid MR induces ROS production and macrophage activation and polarization to the M1 phenotype. (6) MR induces T cell expression of homing markers and differentiation to the Th17 subset. (7) Aldo activation of neutrophil MR induces MMP-9 production, which may promote atherosclerotic plaque rupture.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4585008&req=5

Figure 1: Aldo and MR in vascular inflammation. (1) Aldo induces systemic inflammation in the setting of cardiovascular risk factors. (2) In response to endothelial damage, Aldo acts on EC–MR to induce cytokine and adhesion molecule expression. (3) Cytokines produced by the endothelium and underlying SMCs induce EC adhesion molecule expression and leukocyte recruitment, adhesion, and transmigration. (4) Aldo also acts on EC–MR to induce rearrangement of the actin cytoskeleton, possibly facilitating leukocyte transmigration. (5) Myeloid MR induces ROS production and macrophage activation and polarization to the M1 phenotype. (6) MR induces T cell expression of homing markers and differentiation to the Th17 subset. (7) Aldo activation of neutrophil MR induces MMP-9 production, which may promote atherosclerotic plaque rupture.
Mentions: Atherosclerosis begins with dysfunction of the vascular endothelium. Healthy endothelial cells (ECs) contribute to vasodilation by producing nitric oxide via endothelial nitric oxide synthase (eNOS) activity. Nitric oxide production is impaired early in atherogenesis, and the downstream effects of this can be measured in vivo by tonometry and flow-mediated vasodilation or ex vivo by quantifying achetylcholine-induced vasodilation of arterial rings. Aldo and vascular MR have been recently implicated in the development of endothelial dysfunction in humans with cardiovascular risk factors and in corresponding animal models. Hypertensive African-Americans had impaired endothelial function, as measured by pulse arterial tonography and by ex vivo studies of adipose vessels, which was improved with spironolactone treatment. Conversely, normotensive subjects had impaired endothelial function after Aldo administration, which was also prevented by spironolactone (17). Hypertensive subjects had an associated decrease in arteriolar glucose-6-phosphate dehydrogenase (G6PD) activity compared to non-hypertensives. A potential mechanism is suggested by a prior study demonstrating that Aldo treatment of bovine ECs in vitro and of mice in vivo decreases EC G6PD expression, resulting in excessive production of reactive oxygen species [ROS (18)]. In another study, treatment of diabetics with spironolactone improved coronary flow reserve, as measured by cardiac PET scan, compared to subjects treated with hydrochlorothiazide to achieve the same blood pressure (19). Thus, in patients with risk factors including hypertension and diabetes, endothelial dysfunction appears to be MR dependent (Figure 1).

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