LncRNA MALAT1 induced by hyperglycemia promotes microvascular endothelial cell apoptosis through activation of the miR-7641/TPR axis to exacerbate neurologic damage caused by cerebral small vessel disease.

Background: This study aimed to explore the effect of hyperglycemia-induced long noncoding RNA (lncRNA) metastasis-associated lung carcinoma transcript 1 (MALAT1) on microvascular endothelial cell activity. In addition, we investigated the possible downstream molecular regulatory mechanism in order to provide an adjunctive therapeutic target for the prognostic nerve recovery of cerebral small vessel disease (CSVD).

Methods: A rat model of diabetes was induced by streptozotocin (STZ) injection in combination with a high-energy diet. The mixed model of CSVD and hyperglycemia was prepared by injection of homologous microemboli in vitro. Results of 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide (MTT) assay and enzyme-linked immunosorbent assay (ELISA) showed that the inhibition of lncRNA MALAT1 by siRNA in a high-glucose environment effectively alleviated the cell damage caused by high glucose (HG) and reduced the rate of apoptosis. We found that the upregulation of downstream miR-7641 and TPR (translocated promoter region) reduced the occurrence of cell damage and apoptosis.

Results: The results of neurological deficit score showed that the scores of ICH group, HG group and HG + ICH group were significantly higher than those of Sham group, and the differences were statistically significant. The qPCR results showed that the MALAT1 level of the model group was significantly different from that of the sham group, and the expression levels of damage markers vWF and ICAM-1 were detected by Western blot (WB), which were significantly higher in the model group than in the sham group. The MTT cell activity assay showed that the addition of miR-7641 inhibitor or TPR short hairpin RNA (shRNA) into normally cultured cells reduced cell activity. ELISA results showed that low expression of miR-7641 increased the apoptosis rate of microvascular endothelial cells. Western blot (WB) results showed that the protein expression levels of BAX and cleaved caspase-3 (c-caspase-3) were negatively correlated with miR-7641. The regulation of TPR expression showed similar results.

Conclusions: High blood glucose level induced the increase of lncRNA MALAT1 and regulated the expression of TPR by activating miR-7641 to promote the initiation of apoptosis of microvascular endothelial cells, aggravating the neurological dysfunction caused by CSVD.