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Endothelial Mineralocorticoid Receptors Contribute to Vascular Inflammation in Atherosclerosis in a Sex-Specific Manner

Published on Aug 1, 2019in Arteriosclerosis, Thrombosis, and Vascular Biology6.618
· DOI :10.1161/ATVBAHA.119.312954
M. Elizabeth Moss4
Estimated H-index: 4
(Tufts University),
Qing Lu11
Estimated H-index: 11
(Tufts Medical Center)
+ 5 AuthorsIris Z. Jaffe26
Estimated H-index: 26
(Tufts University)
Sources
Abstract
OBJECTIVE: MR (mineralocorticoid receptor) activation is associated with cardiovascular ischemia in humans. This study explores the role of the MR in atherosclerotic mice of both sexes and identifies a sex-specific role for endothelial cell (EC)-MR in vascular inflammation. Approach and Results: In the AAV-PCSK9 (adeno-associated virus-proprotein convertase subtilisin/kexin type 9) mouse atherosclerosis model, MR inhibition attenuated vascular inflammation in males but not females. Further studies comparing male and female littermates with intact MR or EC-MR deletion revealed that although EC-MR deletion did not affect plaque size in either sex, it reduced aortic arch inflammation specifically in male mice as measured by flow cytometry. Moreover, MR-intact females had larger plaques but were protected from vascular inflammation compared with males. Intravital microscopy of the mesenteric vasculature demonstrated that EC-MR deletion attenuated TNFα (tumor necrosis factor α)-induced leukocyte slow rolling and adhesion in males, while females exhibited fewer leukocyte-endothelial interactions with no additional effect of EC-MR deletion. These effects corresponded with decreased TNFα-induced expression of the endothelial adhesion molecules ICAM-1 (intercellular adhesion molecule-1) and E-selectin in males with EC-MR deletion compared with MR-intact males and females of both genotypes. These observations were also consistent with MR and estrogen regulation of ICAM-1 transcription and E-selectin expression in primary cultured mouse ECs and human umbilical vein ECs.CONCLUSIONS: In male mice, EC-MR deletion attenuates leukocyte-endothelial interactions, plaque inflammation, and expression of E-selectin and ICAM-1, providing a potential mechanism by which the MR promotes vascular inflammation. In females, plaque inflammation and leukocyte-endothelial interactions are decreased relative to males and EC-MR deletion is not protective. (Less)
  • References (39)
  • Citations (4)
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References39
Newest
#1Shu-Lin LiuH-Index: 7
#2Anamika BajpaiH-Index: 3
Last. Richard K. AssoianH-Index: 42
view all 9 authors...
3 CitationsSource
#1M. Elizabeth Moss (Tufts University)H-Index: 4
#2Jennifer J. DuPont (Tufts Medical Center)H-Index: 12
Last. Iris Z. Jaffe (Tufts University)H-Index: 26
view all 5 authors...
5 CitationsSource
#1Emelia J. BenjaminH-Index: 154
#2Salim S. ViraniH-Index: 37
Last. Paul MuntnerH-Index: 92
view all 51 authors...
Each chapter listed in the Table of Contents (see next page) is a hyperlink to that chapter. The reader clicks the chapter name to access that chapter. Each chapter listed here is a hyperlink. Click on the chapter name to be taken to that chapter. Each year, the American Heart Association (AHA), in conjunction with the Centers for Disease Control and Prevention, the National Institutes of Health, and other government agencies, brings together in a single document the most up-to-date statistics r...
1,241 CitationsSource
#1Ana P. Davel (State University of Campinas)H-Index: 1
#2Qing Lu (Tufts Medical Center)H-Index: 11
Last. Iris Z. Jaffe (Tufts Medical Center)H-Index: 26
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BackgroundThe incidence of obesity is rising, particularly among women. Microvascular dysfunction is more common with female sex, obesity, and hyperlipidemia and predicts adverse cardiovascular out...
18 CitationsSource
Animal studies are a foundation for defining mechanisms of atherosclerosis and potential targets of drugs to prevent lesion development or reverse the disease. In the current literature, it is common to see contradictions of outcomes in animal studies from different research groups, leading to the paucity of extrapolations of experimental findings into understanding the human disease. The purpose of this statement is to provide guidelines for development and execution of experimental design and ...
38 CitationsSource
#1Austin C. Boese (Tulane University)H-Index: 4
#2Seong Chul Kim (Tulane University)H-Index: 2
Last. Milton Hamblin (Tulane University)H-Index: 22
view all 5 authors...
Sex differences between women and men are often overlooked and underappreciated when studying the cardiovascular system. It has been long assumed that men and women are physiologically similar, and this notion has resulted in women being clinically evaluated and treated for cardiovascular pathophysiological complications as men. Currently, there is increased recognition of fundamental sex differences in cardiovascular function, anatomy, cell signaling, and pathophysiology. The National Institute...
22 CitationsSource
#1Ane M. Salvador (Tufts University)H-Index: 6
#2M. Elizabeth Moss (Tufts University)H-Index: 4
Last. Pilar Alcaide (Tufts University)H-Index: 24
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Abstract Heart Failure (HF) is associated with increased circulating levels of aldosterone and systemic inflammation. Mineralocorticoid receptor (MR) antagonists block aldosterone action and decrease mortality in patients with congestive HF. However, the molecular mechanisms underlying the therapeutic benefits of MR antagonists remain unclear. MR is expressed in all cell types in the heart, including the endothelial cells (EC), in which aldosterone induces the expression of intercellular adhesio...
11 CitationsSource
#1Sanjay Rajagopalan (UMB: University of Maryland, Baltimore)H-Index: 72
#2M. Amer AlaitiH-Index: 1
Last. Matthew R. Weir (UMB: University of Maryland, Baltimore)H-Index: 27
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Mineralocorticoid receptor (MR) activation plays an essential role in promoting inflammation, fibrosis, and target organ damage. Currently, no studies are investigating MR antagonism in patients with type 2 diabetes mellitus (T2DM) with chronic kidney disease, at high risk for cardiovascular complications, who are otherwise not candidates for MR antagonism by virtue of heart failure. Further, there is limited information on candidate therapies that may demonstrate differential benefit from this ...
3 CitationsSource
#1Vincenzo MarzollaH-Index: 9
#2Andrea ArmaniH-Index: 12
Last. Massimiliano Caprio (OU: Open University)H-Index: 25
view all 11 authors...
Abstract Objective Elevated aldosterone is associated with increased risk of atherosclerosis complications, whereas treatment with mineralocorticoid receptor (MR) antagonists decreases the rate of cardiovascular events. Here we test the hypothesis that aldosterone promotes early atherosclerosis by modulating intercellular adhesion molecule-1 (ICAM-1) expression and investigate the molecular mechanisms by which aldosterone regulates ICAM-1 expression. Methods and results Apolipoprotein-E (ApoE) −...
25 CitationsSource
#1Zhu-Xia Shen (CAS: Chinese Academy of Sciences)H-Index: 3
#2Xiao-Qing Chen (SJTU: Shanghai Jiao Tong University)H-Index: 3
Last. Sheng-Zhong Duan (SJTU: Shanghai Jiao Tong University)H-Index: 6
view all 13 authors...
Abstract Mineralocorticoid receptor (MR) has been considered as a potential target for treating atherosclerosis. However, the cellular and molecular mechanisms are not completely understood. We aim to explore the functions and mechanisms of macrophage MR in atherosclerosis. Atherosclerosis-susceptible LDLRKO chimeric mice with bone marrow cells from floxed control mice or from myeloid MR knock-out (MRKO) mice were generated and fed with high cholesterol diet. Oil red O staining showed that MRKO ...
18 CitationsSource
Cited By4
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#1Feng-Jiao Li (Yunnan University)H-Index: 1
#2Ting Zhang (Yunnan University)H-Index: 1
Last. Jie Yu (Yunnan University)H-Index: 1
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Abstract Ethnopharmacological relevance 2,3,5,4′-Tetrahydroxy-stilbene-2-O-β-D-glucoside (TSG) is the main active component of Polygoni Multiflori Radix, a root of the homonymous plant widely used in traditional Chinese medicine. TSG has protective effects on the liver, reduces cholesterol and possesses anti-oxidant, anti-tumor, and anti-atherosclerotic properties. However, the pharmacological effects and mechanisms of action of Polygonum multiflorum on atherosclerosis (AS) have not been studied...
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#1Gabriel R. Estrela (Paris V: Paris Descartes University)H-Index: 1
#1Gabriel R. Estrela (Paris V: Paris Descartes University)
Last. Frederic Jaisser (Paris V: Paris Descartes University)H-Index: 40
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Cisplatin is a highly successful chemotherapeutic agent used for the treatment of solid tumors. However, nephrotoxicity is a limiting factor that occurs in 30% of patients under treatment. Many mechanisms are involved in cisplatin-induced nephrotoxicity, such as epithelial and endothelial injury, inflammation, oxidative stress, and renal vasoconstriction. The mineralocorticoid receptor (MR) has an important role in inflammation and vascular function. MR blockage and ablation have been shown to b...
Source
#1Stefania GoriniH-Index: 8
Last. Massimiliano Caprio (OU: Open University)H-Index: 25
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The mineralocorticoid receptor (MR) was originally identified as a regulator of blood pressure, able to modulate renal sodium handling in response to its principal ligand aldosterone. MR is also expressed in many tissues other than kidney, including the heart, vasculature and adipose tissue. More recent studies have shown that extra-renal MR plays a relevant role in the control of cardiovascular and metabolic functions and has recently been implicated in the pathophysiology of aging. MR activati...
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#1M. Elizabeth Moss (Tufts University)H-Index: 4
#2Brigett Carvajal (Tufts University)H-Index: 1
Last. Iris Z. Jaffe (Tufts University)H-Index: 26
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Abstract Cardiovascular disease remains the leading cause of death for both men and women. The observation that premenopausal women are protected from cardiovascular disease relative to age-matched men, and that this protection is lost with menopause, has led to extensive study of the role of sex steroid hormones in the pathogenesis of cardiovascular disease. However, the molecular basis for sex differences in cardiovascular disease is still not fully understood, limiting the ability to tailor t...
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