4.7 Article

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

期刊

FASEB JOURNAL
卷 34, 期 2, 页码 2238-2251

出版社

WILEY
DOI: 10.1096/fj.201901995R

关键词

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

资金

  1. American Heart Association-American Stroke Association [0930219N] Funding Source: Medline
  2. HHS | National Institutes of Health (NIH) [HL138023, HL126186, HL134608, HL116729] Funding Source: Medline
  3. NHLBI NIH HHS [R01 HL142627, R01 HL116729, R01 HL138023, R56 HL142627, P01 HL134608, R01 HL126186] Funding Source: Medline
  4. NIDDK NIH HHS [P30 DK079626] Funding Source: Medline

向作者/读者索取更多资源

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 (BMMo) 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 BMMo-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 BMMo HuR expression and its transfer into exosome. The data suggest that HuR might be targeted to alleviate macrophage dysfunction and pathological fibrosis in diabetes.

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