| MicroRNAs are endogenous non-coding RNAs, consisting of about 22 nucleotides in length. They play an important role in regulating gene expression by base-pairing to the complementary sites on the target mRNAs, thus blocking the translation or triggering the degradation of the target mRNAs.Our recent studies demonstrated that miRNAs can be selectively packaged into microvesicles (MVs).MVs are small vesicles that are shed from almost all cell types under both normal and pathological conditions. These secreted MVs bear surface receptors/ligands of the original cells and have the potential to selectively interact with specific target cells. These MVs can enter and deliver miRNAs into target cell, and changed the biological function of the target cell.Type 2 diabetes, generally accompaning insulin resistance, is a complex metabolic syndrome. It is wildly accepted that obesity is likely to be an important risk factor for type 2 diabetes, but the precise mechanism that high free fatty acid caused by obesity leads to type 2 diabetes is still unclear.Recent studies reported that the expression of miR-29 family was upregulated in skeletal muscle, adipose tissue and liver of GK rat, indicating that miR-29 family associate with type 2 diabetes. Our study found that miR-29 family increased in the serum of obese type 2 diabetes patients and ob/ob mice, and in vitro studies showed that high free fatty acid-induced islet secreted miR-29 into serum via MVs to upregulat the level of miR-29 in serum. Meanwhile, in vivo and in vitro studies showed that the secreted miR-29 can enter hepatocyte and decreased the expression of p85a which is an important protein in insulin signaling. Surprisingly, the islet-derived MVs combined with treatment of chronic high free fatty acid decrease p85a expression more effectively and the islet-derived MVs alone decrease p85a expression earlier than that of chronic high free fatty acid. In vivo studies confirmed that of MVs derived from high level free fatty acid-induced MIN6 cells leaded to the insulin resistance of mice via decreasing p85a expression, and further studies showed it was caused by miR-29 family contained in MIN6-derived MVs.Taken together, our results demonstrated that The high free fatty acid can induce the secretion of miRNAs from islet and these miRNAs can enter liver and induce insulin resistance. The MVs derived from high free fatty acid-induced islet may play an early and important role in the development of insulin resistance.Angiogenesis, the formation of new blood vessels from pre-existing endothelium, is a fundamental step in a variety of physiological and pathological conditions including wound healing, embryonic development, chronic inflammation, vessel disease progression, and tumor growth. Some studies has demonstrated that miRNAs can regulate the process of angiogenesis. It was reported that secreted miR-150 derived from human monocyte(THP-1) can induced the migration of endothelial cell, and this result prompted the initial speculation that miRNAs secreted by MVs are implicated in the formation of new blood vessel capillaries during physiological and pathological conditions. Our study demonstrated for the first that secreted miR-150 enhanced the tube formation of human endothelial cells (HMEC-1). in vivo studies found that intravenous injection MVs derived from THP-1 enhanced the angiogenesis in mice model. More importantly, further more we also found that miR-150 contained in THP-1-derived MVs induced the process of angiogenesis. More importantly, MVs isolated from the plasma of patients with atherosclerosis more effectively promoted endothelial cell migration than MVs from healthy donors because these MVs contained a high level of miR-150.Here, we confirmed for the first time that secreted miRNAs stimulates HMEC-1 tube formation in vitro and angiogenesis in vivo. |
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