Histopathological significance of microRNA-210 expression in acute peripheral ischemia in a murine femoral artery ligation model

Abstract

Under hypoxic conditions, microRNA-210 is upregulated and plays multiple physiological roles including in cell growth arrest, stem cell survival, repression of mitochondrial respiration, angiogenesis, and arrest of DNA repair. In this study, we investigated the histopathological expression of microRNA-210 under hypoxic conditions using a femoral artery ligation model established in C57BL/6J mice to determine the pathological significance of microRNA-210. Following femoral artery ligation, ischemia was represented by decreased blood flow compared to the control, in which a sham operation was performed. On histopathology, degeneration/necrosis of the muscle fibers, inflammatory cell infiltration, and regeneration of the muscle fibers were sequentially observed from 3 h to 3 d after ligation of the artery. The degree of these effects was more severe in the area in which type I muscular fibers are dominant. The histological expression of hypoxia-inducible factor 1α, a well-known biomarker of hypoxia, and microRNA-210 was observed in a few necrotic muscle fibers, macrophages, and myoblasts, a distribution consistent with the histopathological lesions, and their signal increased over time. The expression of microRNA-210 in macrophages and myoblasts under ischemia might be indicative of a significant role in the recovery from ischemic lesions. In addition, the in situ hybridization of microRNA-210 could potentially be used for the detection of hypoxia as a histological marker in addition to the immunohistochemistry of hypoxia-inducible factor 1α.

Elevated level of microRNA-210 at the initiation of muscular regeneration in acetic acid-induced non-ischemic skeletal muscular injury in mice

“…Moreover, in this study, the existence of muscular necrosis/degeneration and a few cases of minimal hemorrhage indicated the possibility of focal hypoxia, which could be partially related to the increased expression of Hif1α. However, its contribution was considered less dominant than that observed in the hindlimb ischemia model, wherein a severe reduction in blood flow was noted after arterial ligation 7 , whereas no other histopathological findings indicating circulation impairment were noted in the intact area of the treated muscles in this study. Under hypoxic conditions, HIF-1α can continuously act as a transcriptional factor after transfer to the nucleus, and miRNA-210 expression can be upregulated thereafter 1,33 .…”

“…Upon the expression of HIF, several microRNAs (miRNAs) are upregulated and miR-210 is one of the major hypoxia-inducible miRNAs. 1 miRNA-210 is reported to be highly expressed under hypoxic conditions, such as in the cardiovascular system 3 , brain 4 , skin 5,6 , and tumor tissues 1 , and increased miRNA-210 expression was observed in a peripheral ischemic mouse skeletal muscular injury model 7 . In our previous study, miRNA-210 expression was observed in myoblasts and macrophages 3 days after ischemic muscular injury, indicating its association with muscular regeneration 7 .…”

“…1 miRNA-210 is reported to be highly expressed under hypoxic conditions, such as in the cardiovascular system 3 , brain 4 , skin 5,6 , and tumor tissues 1 , and increased miRNA-210 expression was observed in a peripheral ischemic mouse skeletal muscular injury model 7 . In our previous study, miRNA-210 expression was observed in myoblasts and macrophages 3 days after ischemic muscular injury, indicating its association with muscular regeneration 7 . Zaccagnini et al have reported that miRNA-210 inhibition increased ischemic tissue damage, and miRNA-210 overexpression attenuated tissue damage and the inflammatory response with a reduced number of infiltrative macrophages after hindlimb ischemia 8,9 .…”