Mechanisms linking adipose tissue inflammation to cardiac hypertrophy and fibrosis

Anthony, Sarah; Guarnieri, Adrienne R; Gozdiff, Anamarie; Helsley, Robert N; Owens, A. Phillip; Tranter, Michael

doi:10.1042/cs20190578

Cited by 52 publications

(39 citation statements)

References 218 publications

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“…With the exception of cerebral vessels, PVAT is found almost ubiquitously on vasculature throughout the body and is markedly increased in obesity [ 28 ]. Compared with lean PVAT, obese PVAT secretes more pro-inflammatory adipokines, including TNFα, leptin, IL-6, plasminogen activator, and resistin, which switch PVAT into a pro-inflammatory and pro-oxidative phenotype that promotes atherosclerotic plaque formation and instability, not only in coronary arteries but also in other blood vessels [ 28 , 29 , 30 , 31 , 32 , 33 , 34 ]. In addition, PVAT dysfunction has been related with the deregulation of blood vessels contractility, so the inflammation and oxidative stress abolish PVAT’s natural protective anti-contractile effect, contributing to the development of hypertension [ 35 , 36 , 37 ].…”

Section: Adipose Tissue Dysfunction and Cvdsmentioning

confidence: 99%

Adipokines and Inflammation: Focus on Cardiovascular Diseases

Feijóo‐Bandín

Aragón-Herrera

Moraña-Fernández

et al. 2020

IJMS

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It is well established that adipose tissue, apart from its energy storage function, acts as an endocrine organ that produces and secretes a number of bioactive substances, including hormones commonly known as adipokines. Obesity is a major risk factor for the development of cardiovascular diseases, mainly due to a low grade of inflammation and the excessive fat accumulation produced in this state. The adipose tissue dysfunction in obesity leads to an aberrant release of adipokines, some of them with direct cardiovascular and inflammatory regulatory functions. Inflammation is a common link between obesity and cardiovascular diseases, so this review will summarise the role of the main adipokines implicated in the regulation of the inflammatory processes occurring under the scenario of cardiovascular diseases.

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Section: Adipose Tissue Dysfunction and Cvdsmentioning

confidence: 99%

Adipokines and Inflammation: Focus on Cardiovascular Diseases

Feijóo‐Bandín

Aragón-Herrera

Moraña-Fernández

et al. 2020

IJMS

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“…Both scWAT inflammation and BAT dysfunction have been previously associated with CVD through disparate independent mechanisms (2). In our prior work, we demonstrated the role of adipocyte-specific HuR deletion on the function of BAT, including a full RNA-seq analysis of HuR-dependent gene expression in BAT (1), but found nothing that would suggest a CVD-mediating effect emanating from direct HuR-dependent changes in BAT.…”

Section: Discussionmentioning

confidence: 99%

“…BAT) as well as anatomical location (e.g. visceral vs. subcutaneous) (2). Specifically, accumulation of WAT tends to be more pro-inflammatory in nature, especially under conditions of chronic energy surplus, and exerts deleterious effects on cardiovascular health (19, 55, 59).…”

Section: Introductionmentioning

confidence: 99%

“…Specifically, accumulation of WAT tends to be more pro-inflammatory in nature, especially under conditions of chronic energy surplus, and exerts deleterious effects on cardiovascular health (19, 55, 59). On the other hand, the presence of metabolically active BAT has been demonstrated to positively correlate with myocardial health (2, 63, 72, 74).…”

Section: Introductionmentioning

confidence: 99%

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Adipocyte deletion of the RNA binding protein HuR induces cardiac hypertrophy and fibrosis

Guarnieri

Anthony

Gozdiff

et al. 2021

Preprint

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Adipose tissue continues to gain appreciation for its broad role as an endocrine organ, and disruptions in adipose tissue homeostasis plays a central role in cardiovascular physiology. We have previously shown that expression of the RNA binding protein HuR in adipose tissue mediates energy expenditure, but the potential cardiovascular impacts of this finding have not been explored. We show here that adipose tissue-specific deletion of HuR (Adipo-HuR-/-) is sufficient to induce the spontaneous development of cardiac hypertrophy and fibrosis. Hearts from Adipo-HuR-/- mice have increased left ventricular (LV) ejection fraction, rate of pressure generation, and LV posterior wall thickness that is accompanied by an increase in LV/body weight ratio and hypertrophic gene expression. Furthermore, Adipo-HuR-/- hearts display increased fibrosis by picrosirius red staining and periostin expression. To identify underlying mechanisms, we applied both RNA-seq and weighted gene co-expression network analysis (WGCNA) to define HuR-dependent changes in gene expression as well as significant relationships between adipose tissue gene expression and LV mass. RNA-seq results demonstrate a significant increase in pro-inflammatory gene expression in the subcutaneous white adipose tissue (scWAT) from Adipo-HuR-/- mice that is accompanied by an increase in serum levels of both TNF-α and IL-6. WGCNA identified a significant enrichment in inflammation, apoptosis/cell death, and vesicle-mediated transport genes among those whose expression most significantly associated with CVD in Adipo-HuR-/-. In conclusion, we demonstrate that the loss of HuR expression in adipose tissue promotes the development of cardiac hypertrophy and fibrosis, potentially through modulation of inflammation and vesicle-mediated transport in scWAT.NEW AND NOTEWORTHYThis work demonstrates the spontaneous development of cardiac hypertrophy and fibrosis upon adipose tissue-specific deletion of the RNA binding protein HuR that appears to be mechanistically driven by HuR-dependent changes in inflammatory and extracellular vesicle transport mediating genes in the subcutaneous white adipose tissue. These results suggest that loss of HuR expression in adipose tissue in obesity, as demonstrated in mouse and humans by our group and others, may contribute to obesity-mediated CVD.

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“…In the cardiovascular system, oxidative stress stimulates pathways associated with cardiac hypertrophy that leads to pathological remodeling of the myocardium, impaired systolic function, fibroblast stimulation and the activation of metalloproteinases, ultimately resulting in chronic heart failure [ 53 ]. The oxidative stress and inflammation associated adipocyte dysregulation and the contribution of the adipose-derived signaling molecules to the progression of cardiomyopathy have been examined recently [ 54 , 55 ]. Recent findings from our laboratory also established the crucial role of adipocyte function in the pathophysiology of uremic cardiomyopathy [ 13 ].…”

Section: Discussionmentioning

confidence: 99%

Oxidant-Induced Alterations in the Adipocyte Transcriptome: Role of the Na,K-ATPase Oxidant Amplification Loop

Sodhi

Denvir

Liu

et al. 2020

IJMS

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(1) Background: Recently we have noted that adipocyte specific expression of the peptide, NaKtide, which was developed to attenuate the Na,K-ATPase oxidant amplification loop, could ameliorate the phenotypical features of uremic cardiomyopathy. We performed this study to better characterize the cellular transcriptomes that are involved in various biological pathways associated with adipocyte function occurring with renal failure. (2) Methods: RNAseq was performed on the visceral adipose tissue of animals subjected to partial nephrectomy. Specific expression of NaKtide in adipocytes was achieved using an adiponectin promoter. To better understand the cause of gene expression changes in vivo, 3T3L1 adipocytes were exposed to indoxyl sulfate (IS) or oxidized low density lipoprotein (oxLDL), with and without pNaKtide (the cell permeant form of NaKtide). RNAseq was also performed on these samples. (3) Results: We noted a large number of adipocyte genes were altered in experimental renal failure. Adipocyte specific NaKtide expression reversed most of these abnormalities. High correlation with some cardiac specific phenotypical features was noted amongst groups of these genes. In the murine adipocytes, both IS and oxLDL induced similar pathway changes as were noted in vivo, and pNaKtide appeared to reverse these changes. Network analysis demonstrated tremendous similarities between the network revealed by gene expression analysis with IS compared with oxLDL, and the combined in vitro dataset was noted to also have considerable similarity to that seen in vivo with experimental renal failure. (4) Conclusions: This study suggests that the myriad of phenotypical features seen with experimental renal failure may be fundamentally linked to oxidant stress within adipocytes.

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Mechanisms linking adipose tissue inflammation to cardiac hypertrophy and fibrosis

Cited by 52 publications

References 218 publications

Adipokines and Inflammation: Focus on Cardiovascular Diseases

Adipokines and Inflammation: Focus on Cardiovascular Diseases

Adipocyte deletion of the RNA binding protein HuR induces cardiac hypertrophy and fibrosis

Oxidant-Induced Alterations in the Adipocyte Transcriptome: Role of the Na,K-ATPase Oxidant Amplification Loop

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