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

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.

Researchers at the University of Alabama at Birmingham School of Medicine evaluated 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. 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.

Injection of diabetic (db/db) BMMØ‐exosomes with HuR deficiency
limits ANG‐II‐induced cardiac fibrosis in mice

exosomes

A‐C, Masson’s trichrome staining and analysis showing lower perivascular and interstitial fibrosis in hearts or mice receiving diabetic (db/db) BMMØ‐exosomes with HuR deficiency (Exo‐db/dbHuR KD), as compared to db/db‐Exo injected mice. Twenty‐eight days post‐administration. n = 3, *P < .01; scale bar, 20 μm. D,E, Echocardiography analysis showing improvements in heart function as shown by higher % ejection fraction and % fractional shortening in mice receiving Exo‐db/dbHuR KD. n = 3, *P < .05. F, Schematic model depicting Exosome‐HuR regulation of fibrogenesis in diabetic heart failure. Diabetes increases HuR expression and cytoplasmic translocation in activated macrophages. The secreted exosome‐associated HuR is then transferred into fibroblasts. The macrophage‐derived HuR increases mRNA stability and expression of inflammatory and fibrogenesis‐related signals thus leading to cardiac fibrosis and dysfunction

Govindappa PK, Patil M, Garikipati VNS, Verma SK, Saheera S, Narasimhan G, Zhu W, Kishore R, Zhang J, Krishnamurthy P. (2019) Targeting exosome-associated human antigen R attenuates fibrosis and inflammation in diabetic heart. FASEB J [Epub ahead of print]. [article]

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