Adipocyte-specific deletion of HuR induces spontaneous cardiac hypertrophy and fibrosis

Abstract

Adipose tissue homeostasis plays a central role in cardiovascular physiology, and the presence of thermogenically active brown adipose tissue (BAT) has recently been associated with cardiometabolic health. We have previously shown that adipose tissue-specific deletion of HuR (Adipo-HuR-/-) reduces BAT-mediated adaptive thermogenesis, and the goal of this work was to identify the cardiovascular impacts of Adipo-HuR-/-. We found that Adipo-HuR-/- mice exhibit a hypercontractile phenotype that is accompanied by increased left ventricle wall thickness and hypertrophic gene expression. Furthermore, hearts from Adipo-HuR-/- display increased fibrosis via picrosirius red staining and periostin expression. To identify underlying mechanisms, we applied both RNA-seq and weighted gene co-expression network analysis (WGCNA) across both cardiac and adipose tissue to define HuR-dependent changes in gene expression as well as significant relationships between adipose tissue gene expression and cardiac fibrosis. RNA-seq results demonstrated a significant increase in pro-inflammatory gene expression in both cardiac and subcutaneous white adipose tissue (scWAT) from Adipo-HuR-/- mice that is accompanied by an increase in serum levels of both TNF-ᵯC; and IL-6. In addition to inflammation-related genes, WGCNA identified a significant enrichment in extracellular vesicle-mediated transport and exosome-associated genes in scWAT whose expression most significantly associated with degree of cardiac fibrosis observed in Adipo-HuR-/- mice, implicating these processes as a likely adipose-to-cardiac paracrine mechanism. These results are significant in that they demonstrate the spontaneous onset of cardiovascular pathology in an adipose tissue-specific gene deletion model and contribute to our understanding of how disruptions in adipose tissue homeostasis may mediate cardiovascular disease.

HuR-dependent expression of Wisp1 is necessary for TGFβ-induced cardiac myofibroblast activity

“…RNA sequencing of paired end 100bp reads at a depth of ~30M reads/sample was performed by the Cincinnati Children’s Hospital Medical Center DNA Sequencing and Genotyping Core. Sequence read mapping and differential expression analysis was done using CLC Genomics Workbench v21.0.3 (Qiagen) as we have done previously [3,16,24]. The single cell RNA-seq dataset using isolated fibroblasts from post-MI hearts has been previously described and is publicly available (NCBI GEO Database accession GSE83337) [25].…”

“…The single cell RNA-seq dataset using isolated fibroblasts from post-MI hearts has been previously described and is publicly available (NCBI GEO Database accession GSE83337) [25]. Correlation analysis of gene co-expression within this dataset was done using transcriptome-wide Pearson correlation (statistical significance cutoff at P ≤ 0.05) modified from the WGCNA R-package (R v4.1.0) as previously described [24,26]…”

“…Sequence read mapping and differential expression analysis was done using CLC Genomics Workbench v21.0.3 (Qiagen) as we have done previously [3,16,24]. The single cell RNA-seq dataset using isolated fibroblasts from post-MI hearts has been previously described and is publicly available (NCBI GEO Database accession GSE83337) [25].…”

CMLD-2 Attenuates Myofibroblast Activation and Bleomycin-Induced Pulmonary Fibrosis in Mice through Antagonizing ELAVL1-Mediated Osteopontin mRNA Stabilization

“…HuR is significantly accumulated in stimulated human lung fibroblasts, IPF lungs and mouse lungs of experimental pulmonary fibrosis; HuR knockdown affected the mRNA stability of ACTA2 36 . However, despite numerous studies are favoring the profibrotic role of HuR, recent studies also show that HuR might serve as protective factors against cardiac remodeling and liver fibrosis 37,38 . Therefore, it still warrants for further investigation about the sophisticated molecular function, the post-translational modification as well as the druggability of HuR in pulmonary fibrosis.…”

Metabolically stressed adipocytes: mediators of cardioprotection via extracellular vesicle-mediated transport of oxidatively damaged mitochondria

“…This work is also of particular interest to my laboratory as we recently demonstrated that adipocyte-specific deletion of the RNA binding protein HuR (Adipo-HuR −/− ) elicits spontaneous cardiac hypertrophy and fibrosis ( 18 ), and additionally have expertise in the field of cardiac preconditioning ( 19 ) and ischemic injury ( 20 , 21 ). Results from our Adipo-HuR −/− mice are suggestive of an endocrine EV driven mechanism of cardiac pathology, and work is ongoing to characterize the HuR-dependent cargo loading of Adipo-EVs from these mice, but given its nature as an RNA binding protein, the mediating factors are likely to be RNA.…”