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

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.

• Authors: Prem Kumar Govindappa, Mallikarjun Patil, Venkata Naga Srikanth Garikipati, Suresh K Verma, Sherin Saheera, Gayathri Narasimhan, Wuqiang Zhu, Raj Kishore, Jianyi Zhang, Prasanna Krishnamurthy
• Journal: FASEB journal : official publication of the Federation of American Societies for Experimental Biology (FASEB J) Vol. 34 Issue 2 Pg. 2238-2251 (02 2020) ISSN: 1530-6860 [Electronic] United States
• PMID: 31907992 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2019 Federation of American Societies for Experimental Biology.

Chemical References

• ELAV-Like Protein 1
• Elavl1 protein, mouse

Topics

• Animals
• Diabetic Cardiomyopathies (genetics, metabolism, pathology, therapy)
• ELAV-Like Protein 1 (genetics, metabolism)
• Fibrosis
• Gene Knockdown Techniques
• Humans
• Inflammation (genetics, metabolism, pathology)
• Macrophages (metabolism, pathology)
• Mice
• Mice, Transgenic
• Myocardium (metabolism, pathology)
• RAW 264.7 Cells