MiR-335 Regulates Hif-1α to Reduce Cell Death in Both Mouse Cell Line and Rat Ischemic Models

Abstract

Hypoxia inducible factor-1α facilitates cellular adaptation to hypoxic conditions. Hence its tight regulation is crucial in hypoxia related diseases such as cerebral ischemia. Changes in hypoxia inducible factor-1α expression upon cerebral ischemia influence the expression of its downstream genes which eventually determines the extent of cellular damage. MicroRNAs are endogenous regulators of gene expression that have rapidly emerged as promising therapeutic targets in several diseases. In this study, we have identified miR-335 as a direct regulator of hypoxia inducible factor-1α and as a potential therapeutic target in cerebral ischemia. MiR-335 and hypoxia inducible factor-1α mRNA showed an inverse expression profile, both in vivo and in vitro ischemic conditions. Given the biphasic nature of hypoxia inducible factor-1α expression during cerebral ischemia, miR-335 mimic was found to reduce infarct volume in the early time (immediately after middle cerebral artery occlusion) of embolic stroke animal models while the miR-335 inhibitor appears to be beneficial at the late time of stroke (24 hrs after middle cerebral artery occlusion). Modulation of hypoxia inducible factor-1α expression by miR-335 also influenced the expression of crucial genes implicated in neurovascular permeability, cell death and maintenance of the blood brain barrier. These concerted effects, resulting in a reduction in infarct volume bring about a beneficial outcome in ischemic stroke.

MicroRNAs in Hyperglycemia Induced Endothelial Cell Dysfunction

“…We found that the expression of miR-140-5p to be increased in IFG as well as in T2DM, in both the human and rat miRNA microarray analyses, as well as in our in vitro study, where miR-140-5p level increased with increasing glucose concentrations ( Table 1 and Table S2 [ 72 , 87 , 88 , 89 , 90 , 91 , 92 , 93 , 94 , 95 , 96 , 97 , 98 , 99 , 100 , 101 , 102 , 103 , 104 , 105 , 106 , 107 , 108 , 109 , 110 , 111 , 112 , 113 , 114 , 115 , 116 , 117 , 118 , 119 , 120 , 121 , 122 , 123 , 124 , 125 , 126 , 127 , 128 , 129 , 130 , 131 , 132 , 133 , 134 , 135 ]). This increase was also found to correlate with the increase in apoptosis ( Figure 2 ).…”

“…Post hoc test was performed with Bonferroni correction to determine the difference between the different groups. Hierarchical clustering (HCL) and k-means clustering were performed using TIGR MeV (TMeV) software and Partek ® Genomics Suite™ 6.6 Software [ 133 , 134 ].…”

Angiogenesis in Ischemic Stroke and Angiogenic Effects of Chinese Herbal Medicine

“…Interestingly, overexpression of miR-210 has been found to be associated with angiogenesis in the brain of adult non ischemic mice with an up-regulation of VEGF [ 50 ]. In a rat model of middle cerebral artery occlusion, miR-139 and miR-335 were found to be down-regulated in the endothelial cells [ 51 , 52 ]. Both miR-139 and miR-335 are closely associated with stroke-induced angiogenesis via ROCK1 and ROCK2 signalling (both ROCK1 and ROCK2 are VEGF signalling regulators) [ 49 ].…”

MicroRNA-18a regulates invasive meningiomas via hypoxia-inducible factor-1α

“…A number of studies have focused on regulatory factors that target HIF-1α. For example, microRNA-18a (miR-18a) has been observed to regulate the expression of HIF-1α in certain tumor tissues (7)(8)(9). However, to the best of our knowledge, the effects of miR-18a on HIF-1α expression in invasive meningiomas has not previously been reported.…”