Mineralocorticoid receptor blockade normalizes coronary resistance in obese swine independent of functional alterations in Kv channels

Goodwill, Adam G.; Baker, Hana E.; Dick, Gregory M.; McCallinhart, Patricia E.; Bailey, Chastidy A.; Brown, Scott M.; Man, Joshua; Tharp, Darla L.; Clark, Howard; Blaettner, Bianca S.; Jaffe, Iris Z.; Bowles, Douglas K.; Trask, Aaron J.; Tune, Johnathan D.; Bender, Shawn B.

doi:10.1007/s00395-021-00879-3

Cited by 9 publications

(4 citation statements)

References 53 publications

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“…Involvement of MR signaling in obesity-associated cardiovascular morbidity and mortality is supported by both clinical and preclinical work, from us 11,12,15,32,33 and others 13,14,34 , utilizing MR antagonists. In obese rodent and swine models, MR blockade with spironolactone or eplerenone mitigated endothelial dysfunction and vascular remodeling as well as diastolic dysfunction, cardiac oxidative stress, fibrosis, and inflammation 11,12,15,[32][33][34] . Mechanistically, several prior studies have revealed an important role for EC MR signaling underlying vascular and cardiac dysfunction in obesity.…”

Section: Discussionmentioning

confidence: 97%

Multi-omic analysis of the cardiac cellulome defines a vascular contribution to cardiac diastolic dysfunction in obese female mice

Dona

Hsu

Meuth

et al. 2022

Preprint

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Coronary microvascular dysfunction (CMD) is associated with cardiac dysfunction and predictive of cardiac mortality in obesity, especially in females. Emerging evidence suggests development of heart failure with preserved ejection fraction in females with CMD and that mineralocorticoid receptor (MR) antagonism may be more efficacious in obese female, versus male, HFpEF patients. Accordingly, we examined the hypothesis that smooth muscle cell (SMC)-specific MR deletion prevents obesity-associated coronary and cardiac diastolic dysfunction in females. Obesity was induced in female mice via western diet (WD) feeding alongside littermates fed standard diet. Initial studies revealed that global MR blockade with spironolactone prevented impaired coronary vasodilation and diastolic dysfunction in obese females. Importantly, specific deletion of SMC-MR similarly prevented obesity-associated coronary and cardiac dysfunction. Cardiac gene expression profiling suggested reduced cardiac inflammation in WD-fed mice with SMC-MR deletion independent of blood pressure, aortic stiffening, and cardiac hypertrophy. Further mechanistic studies utilizing single-cell RNA sequencing of non-cardiomyocyte cell populations revealed novel impacts of SMC-MR deletion on the cardiac cellulome in obese mice. Specifically, WD feeding induced inflammatory gene signatures in multiple non-myocyte populations (B/T cells, macrophages, and endothelium), independent of cardiac fibrosis, that was prevented by SMC-MR deletion. Further, SMC-MR deletion induced a basal reduction in cardiac mast cells and prevented WD-induced cardiac pro-inflammatory chemokine expression and leukocyte recruitment. These data reveal a central role for SMC-MR signaling in obesity-associated coronary and cardiac dysfunction thus supporting the emerging paradigm of a vascular origin of cardiac dysfunction in obesity.

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Section: Discussionmentioning

confidence: 97%

Multi-omic analysis of the cardiac cellulome defines a vascular contribution to cardiac diastolic dysfunction in obese female mice

Dona

Hsu

Meuth

et al. 2022

Preprint

Self Cite

View full text Add to dashboard Cite

show abstract

“…Involvement of MR signaling in obesity-associated cardiovascular morbidity and mortality is supported by both clinical and preclinical work, from us [ 4 , 6 , 7 , 13 , 21 ] and others [ 19 , 33 , 53 ], utilizing MR antagonists. In obese rodent and swine models, MR blockade with spironolactone or eplerenone mitigated endothelial dysfunction and vascular remodeling as well as diastolic dysfunction, cardiac oxidative stress, fibrosis, and inflammation [ 4 , 6 , 7 , 13 , 21 , 53 ]. Mechanistically, several prior studies have revealed an important role for EC MR signaling underlying vascular and cardiac dysfunction in obesity.…”

Section: Discussionmentioning

confidence: 98%

Multi-omic analysis of the cardiac cellulome defines a vascular contribution to cardiac diastolic dysfunction in obese female mice

et al. 2023

Self Cite

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Coronary microvascular dysfunction (CMD) is associated with cardiac dysfunction and predictive of cardiac mortality in obesity, especially in females. Clinical data further support that CMD associates with development of heart failure with preserved ejection fraction and that mineralocorticoid receptor (MR) antagonism may be more efficacious in obese female, versus male, HFpEF patients. Accordingly, we examined the impact of smooth muscle cell (SMC)-specific MR deletion on obesity-associated coronary and cardiac diastolic dysfunction in female mice. Obesity was induced in female mice via western diet (WD) feeding alongside littermates fed standard diet. Global MR blockade with spironolactone prevented coronary and cardiac dysfunction in obese females and specific deletion of SMC-MR was sufficient to prevent obesity-associated coronary and cardiac diastolic dysfunction. Cardiac gene expression profiling suggested reduced cardiac inflammation in WD-fed mice with SMC-MR deletion independent of blood pressure, aortic stiffening, and cardiac hypertrophy. Further mechanistic studies utilizing single-cell RNA sequencing of non-cardiomyocyte cell populations revealed novel impacts of SMC-MR deletion on the cardiac cellulome in obese mice. Specifically, WD feeding induced inflammatory gene signatures in non-myocyte populations including B/T cells, macrophages, and endothelium as well as increased coronary VCAM-1 protein expression, independent of cardiac fibrosis, that was prevented by SMC-MR deletion. Further, SMC-MR deletion induced a basal reduction in cardiac mast cells and prevented WD-induced cardiac pro-inflammatory chemokine expression and leukocyte recruitment. These data reveal a central role for SMC-MR signaling in obesity-associated coronary and cardiac dysfunction, thus supporting the emerging paradigm of a vascular origin of cardiac dysfunction in obesity.

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“…Mineralocorticoid receptor (MR) activation promotes inflammation, oxidative stress, obesity-associated coronary microvascular dysfunction, cardiac and arterial fibrotic remodeling and calcification [ 2 , 8 , 9 , 28 , 33 ]. Experimental studies using cell-selective MR-null or MR-overexpressing transgenic mice emphasized the cell-specific function of the MR in the cardiovascular system and identified the central role of MR signaling in macrophages in inflammatory and fibrotic mechanisms [ 7 , 22 , 29 , 57 ].…”

Section: Introductionmentioning

confidence: 99%

Mineralocorticoid receptor promotes cardiac macrophage inflammaging

Fraccarollo,

Geffers,

Galuppo

et al. 2024

Basic Res Cardiol

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Inflammaging, a pro-inflammatory status that characterizes aging and primarily involving macrophages, is a master driver of age-related diseases. Mineralocorticoid receptor (MR) activation in macrophages critically regulates inflammatory and fibrotic processes. However, macrophage-specific mechanisms and the role of the macrophage MR for the regulation of inflammation and fibrotic remodeling in the aging heart have not yet been elucidated. Transcriptome profiling of cardiac macrophages from male/female young (4 months-old), middle (12 months-old) and old (18 and 24 months-old) mice revealed that myeloid cell-restricted MR deficiency prevents macrophage differentiation toward a pro-inflammatory phenotype. Pathway enrichment analysis showed that several biological processes related to inflammation and cell metabolism were modulated by the MR in aged macrophages. Further, transcriptome analysis of aged cardiac fibroblasts revealed that macrophage MR deficiency reduced the activation of pathways related to inflammation and upregulation of ZBTB16, a transcription factor involved in fibrosis. Phenotypic characterization of macrophages showed a progressive replacement of the TIMD4+MHC-IIneg/low macrophage population by TIMD4+MHC-IIint/high and TIMD4–MHC-IIint/high macrophages in the aging heart. By integrating cell sorting and transwell experiments with TIMD4+/TIMD4–macrophages and fibroblasts from old MRflox/MRLysMCre hearts, we showed that the inflammatory crosstalk between TIMD4– macrophages and fibroblasts may imply the macrophage MR and the release of mitochondrial superoxide anions. Macrophage MR deficiency reduced the expansion of the TIMD4– macrophage population and the emergence of fibrotic niches in the aging heart, thereby protecting against cardiac inflammation, fibrosis, and dysfunction. This study highlights the MR as an important mediator of cardiac macrophage inflammaging and age-related fibrotic remodeling.

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Mineralocorticoid receptor blockade normalizes coronary resistance in obese swine independent of functional alterations in Kv channels

Cited by 9 publications

References 53 publications

Multi-omic analysis of the cardiac cellulome defines a vascular contribution to cardiac diastolic dysfunction in obese female mice

Multi-omic analysis of the cardiac cellulome defines a vascular contribution to cardiac diastolic dysfunction in obese female mice

Multi-omic analysis of the cardiac cellulome defines a vascular contribution to cardiac diastolic dysfunction in obese female mice

Mineralocorticoid receptor promotes cardiac macrophage inflammaging

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