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MiR-29b Mediates the Chronic Inflammatory Response in Radiotherapy-Induced Vascular Disease.

ABSTRACT: As a consequence of the success of present-day cancer treatment, radiotherapy-induced vascular disease is emerging. This disease is caused by chronic inflammatory activation and is likely orchestrated in part by microRNAs. In irradiated versus nonirradiated conduit arteries from patients receiving microvascular free tissue transfer reconstructions, irradiation resulted in down-regulation of miR-29b and up-regulation of miR-146b. miR-29b affected inflammation and adverse wound healing through its targets pentraxin-3 and dipeptidyl-peptidase 4. In vitro and in vivo, we showed that miR-29b overexpression therapy, through inhibition of pentraxin-3 and dipeptidyl-peptidase 4, could dampen the vascular inflammatory response.

SUBMITTER: Eken SM

PROVIDER: S-EPMC6390501 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature

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miR-29b Mediates the Chronic Inflammatory Response in Radiotherapy-Induced Vascular Disease.

Eken Suzanne M SM Christersdottir Tinna T Winski Greg G Sangsuwan Traimate T Jin Hong H Chernogubova Ekaterina E Pirault John J Sun Changyan C Simon Nancy N Winter Hanna H Backlund Alexandra A Haghdoost Siamak S Hansson Göran K GK Halle Martin M Maegdefessel Lars L

JACC. Basic to translational science 20190225 1

As a consequence of the success of present-day cancer treatment, radiotherapy-induced vascular disease is emerging. This disease is caused by chronic inflammatory activation and is likely orchestrated in part by microRNAs. In irradiated versus nonirradiated conduit arteries from patients receiving microvascular free tissue transfer reconstructions, irradiation resulted in down-regulation of miR-29b and up-regulation of miR-146b. miR-29b affected inflammation and adverse wound healing through its ...[more]

PMID: 30847421

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Project description:The Na/K-ATPase is an important membrane ion transporter and a signaling receptor that is essential for maintaining normal cell function. The current study examined the role of Na/K-ATPase signaling in regulating miR-29b-3p, an anti-fibrotic microRNA, in a mouse chronic kidney disease (CKD) model (5/6th partial nephrectomy or PNx). The results showed that CKD induced significant reduction of miR-29b-3p expression in the heart tissue by activation of Src and NF?B signaling in these animals. To demonstrate the role of Na/K-ATPase signaling, we also performed the PNx surgery on Na/K-ATPase ?1 heterozygous (?1+/-) mice, which expresses ~40% less Na/K-ATPase ?1 compared to their wild type littermates (WT) and exhibits deficiency in Na/K-ATPase signaling. We found that CKD did not significantly change the miR-29b-3p expression in heart tissue from the ?1+/- animals. We also found that CKD failed to activate Src and NF?B signaling in these animals. Using isolated cardiac fibroblasts from ?1+/- mice and their WT littermates, we showed that ouabain, a specific Na/K-ATPase ligand, induces decreased miR-29b-3p expression in fibroblasts isolated from WT mice, but had no effect in cells from ?1+/- mice. Inhibition of NF?B by Bay11-7082 prevented ouabain-induced miR-29b-3p reduction in WT fibroblasts. To further confirm the in vivo effect of Na/K-ATPase signaling in regulation of miR-29b-3p and cardiac fibrosis in CKD animals, we used pNaKtide, a Src inhibiting peptide derived from the sequence of Na/K-ATPase, to block the activation of Na/K-ATPase signaling. The result showed that pNaKtide injection significantly increased miR-29b-3p expression and mitigated the CKD-induced cardiac fibrosis in these animals. These results clearly demonstrated that Na/K-ATPase signaling is an important mediator in CKD that regulates miR-29b-3p expression and cardiac fibrosis, which provides a novel target for regulation of miR-29b-3p in CKD. We also demonstrate that antagonizing Na/K-ATPase signaling by pNaKtide can reduce organ fibrosis through the stimulation of tissue miR-29b-3p expression.

Project description:An association between lower bone mineral density (BMD) and presence of vascular calcification (VC) has been reported in several studies. Chronic kidney disease (CKD) causes detrimental disturbances in the mineral balance, bone turnover, and development of severe VC. Our group has previously demonstrated expression of Wnt inhibitors in calcified arteries of CKD rats. Therefore, we hypothesized that the CKD-induced VC via this pathway signals to bone and induces bone loss. To address this novel hypothesis, we developed a new animal model using isogenic aorta transplantation (ATx). Severely calcified aortas from uremic rats were transplanted into healthy rats (uremic ATx). Transplantation of normal aortas into healthy rats (normal ATx) and age-matched rats (control) served as control groups. Trabecular tissue mineral density, as measured by μCT, was significantly lower in uremic ATx rats compared with both control groups. Uremic ATx rats showed a significant upregulation of the mineralization inhibitors osteopontin and progressive ankylosis protein homolog in bone. In addition, we found significant changes in bone mRNA levels of several genes related to extracellular matrix, bone turnover, and Wnt signaling in uremic ATx rats, with no difference between normal ATx and control. The bone histomorphometry analysis showed significant lower osteoid area in uremic ATx compared with normal ATx along with a trend toward fewer osteoblasts as well as more osteoclasts in the erosion lacunae. Uremic ATx and normal ATx had similar trabecular number and thickness. The bone formation rate did not differ between the three groups. Plasma biochemistry, including sclerostin, kidney, and mineral parameters, were similar between all three groups. ex vivo cultures of aorta from uremic rats showed high secretion of the Wnt inhibitor sclerostin. In conclusion, the presence of VC lowers BMD, impairs bone metabolism, and affects several pathways in bone. The present results prove the existence of a vasculature to bone tissue cross-talk. © 2020 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

Dataset Information

MiR-29b Mediates the Chronic Inflammatory Response in Radiotherapy-Induced Vascular Disease.

Publications

miR-29b Mediates the Chronic Inflammatory Response in Radiotherapy-Induced Vascular Disease.

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