Targeting exosome-associated human antigen R attenuates fibrosis and inflammation in diabetic heart

Prem Kumar Govindappa, Mallikarjun Patil, Venkata Naga Srikanth Garikipati, Suresh K. Verma, Sherin Saheera, Gayathri Narasimhan, Wuqiang Zhu, Raj Kishore, Jianyi Zhang, Prasanna Krishnamurthy

Research output: Contribution to journalArticlepeer-review

4 Scopus citations

Abstract

RNA-binding proteins like human antigen R (HuR) are key regulators in post-transcriptional control of gene expression in several pathophysiological conditions. Diabetes adversely affects monocyte/macrophage biology and function. It is not known whether diabetic milieu affects cellular/exosome-HuR and its implications on cardiac inflammation and fibrosis. Here, we evaluate in vitro and in vivo effects of diabetic milieu on macrophage cellular/exosome-HuR, alterations in intercellular cross talk with fibroblasts, and its impact on cardiac remodeling. Human failing hearts show higher HuR levels. Diabetic milieu activates HuR expression in cardiac- and cultured bone marrow-derived macrophages (BMMØ) and stimulates HuR nuclear-to-cytoplasmic translocation and exosome transfer. Exosomes from macrophages exposed to diabetic milieu (high glucose or db/db mice) significantly increase inflammatory and profibrogenic responses in fibroblast (in vitro) and cardiac fibrosis in mice. Intriguingly, Exo-HuR deficiency (HuR knockdown in macrophage) abrogates the above effects. In diabetic mice, macrophage depletion followed by reconstitution with BMMØ-derived HuR-deficient exosomes inhibits angiotensin II-induced cardiac fibrosis response and preserves left ventricle function as compared to control-exosome administration. To the best of our knowledge, this is the first study to demonstrate that diabetes activates BMMØ HuR expression and its transfer into exosome. The data suggest that HuR might be targeted to alleviate macrophage dysfunction and pathological fibrosis in diabetes.

Original languageEnglish (US)
Pages (from-to)2238-2251
Number of pages14
JournalFASEB Journal
Volume34
Issue number2
DOIs
StatePublished - Feb 1 2020

Keywords

  • cardiac fibrosis
  • cardiac inflammation
  • diabetes
  • exosome
  • HuR
  • intercellular signaling

ASJC Scopus subject areas

  • Biotechnology
  • Biochemistry
  • Molecular Biology
  • Genetics

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