Abstract
Although a large number of studies have confirmed from multiple levels that diabetes mellitus (DM) promotes cerebral ischemic reperfusion (I/R) injury, but the precise mechanism is still unclear. A cerebral I/R injury model in diabetic rats was established. The neurological deficit scores and brain edema were monitored at 24 and 72 hours after injury. The peri-infarct cortical tissues of rats were isolated for molecular biology detection. The rat primary microglia and microglia line HAPI were cultured to establish the cell model of DM-I/R by high glucose (HG) and hypoxia-reoxygenation (H/R). The endogenous expression of MALAT1 and MyD88 was regulated by the transfection with pcDNA-MALAT1, si-MALAT1 and si-MyD88, respectively. The cerebral I/R injury model in diabetic rats had more severe neuronal injury as shown by the significantly higher neurological deficit scores and an obvious increasing brain edema at 24 and 72 hours after injury. Moreover, the microglia were activated and induced a large number of inflammatory cytokines TNF-α, IL-1β and IL-6 in the peri-infarct cortical tissues during cerebral I/R injury associated with DM. The expression of MALAT1, MyD88, IRAK1 and TRAF6 protein were significantly up-regulated by DM-I/R in vitro and in vivo. Furthermore, the HG-H/R-induced MALAT1 promoted the inflammatory response in microglia via MyD88/IRAK1/TRAF6 signaling. Our results suggested that MALAT1 mediated the exacerbation of cerebral I/R injury induced by DM through triggering the inflammatory response in microglia via MyD88 signaling.
Highlights
Cerebrovascular disease has the characteristics of high incidence, disability rate and mortality rate that seriously damage the health of human[1]
It was observed that the expressions of the pro-inflammatory cytokines TNF-α, IL-1β and interleukin 6 (IL-6) were dramatically increased in the peri-infarct cortical tissues of diabetes mellitus (DM)-ischemic reperfusion (I/R) rats (n = 6) compared with the control (n = 6) and cerebral I/R injury rats (n = 6) (Fig. 1C–F)
Microglia is the main inflammatory cell that participates in the pathological environment of cerebral I/R injury, which can secrete a large amounts of inflammatory cytokines, resulting in serious inflammation reaction[14]
Summary
Cerebrovascular disease has the characteristics of high incidence, disability rate and mortality rate that seriously damage the health of human[1]. It was found that MALAT1 mediated the glucose-induced inflammatory cytokine production, including tumour necrosis factor alpha (TNF-α) and interleukin 6 (IL-6), in the endothelial cells, which may lead to the development of DM-induced vascular complications[9]. MALAT1 was dramatically increased in the kidneys of diabetic mice accompanied by a relatively high level in IL-6 and TNF-α mRNA9. We hypothesized that lncRNA MALAT1 participated in the pathogenesis of the cerebral ischemic reperfusion injury induced by DM, the mechanism of which may be related to the MyD88-mediated inflammatory response in microglia
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