In the heart, where EndMT was first demonstrated, it has been shown that this transition of endothelial cells is key to the formation of cardiac valves during development.
14 Additionally, such process may act as a key switch in cardiac fibrosis in various diseases and provide potential treatment target.
9,10 Transforming growth factor β signaling pathway through Smad and Snail converge in the cell nucleus to change the transcriptional machinery.
36 It has been demonstrated that oxidative stress may be a key initiating factor in such process in other tissues.
43,44 We also used serum-free condition in our assays to avoid effects of TGFβ or other growth factors in the serum. It should be noted that overt fibrosis, as in diabetic nephropathy or cardiomyopathy, is not observed in the retina in diabetes. However, increased production of ECM proteins and endothelial dysfunctions are well-established features of retinal affection in diabetes.
5,6,26,27 The data generated from the current study indicate molecular and phenotypic changes linking these processes. Results of the current study further indicate involvement of specific transcriptional machinery in retinal EndMT in diabetes. We have previously demonstrated the role of miR-200b in augmented VEGF production in diabetes.
28 Here we have shown that the same miR also modulates EndMT through modulation of signaling molecules in the TGFβ pathway. The miR-200b also regulates production of transcription coactivator p300.
28 The p300 alteration has been shown in cardiac EndMT.
24 In addition, p300 has been thought to be a master regulator of transcriptional machinery.
8,9,26,45 Conceptually, through P300, miR-200b may regulate multiple molecules. As shown in in vitro studies and in the experiments using endothelial-specific miR-200b transgenic mice, we have demonstrated such phenomena. We have also demonstrated earlier that other members on the miR200 cluster may not be involved in such process.
28 In addition, this study has further supported the important role played by endothelial cells in the pathogenesis of molecular changes in diabetic retinopathy.
28,40,46 This study further opens up new targets to block EndMT. Based on the results of this study, either miR-200b or p300 may act as potential targets to prevent these changes. The miR-200b, being a regulator of p300 as shown in this study and in other studies, may actually lend itself as a target of RNA-based therapeutics in the context of early molecular changes in the retina in diabetes. Such an approach may be beneficial to block changes like EndMT, as shown in this study, or augmented production of VEGF as demonstrated by us previously.
28 However, whether such an approach may indeed be beneficial in established diabetic retinopathy needs to be further validated by carefully conducted long-term studies. A diagrammatic outline of the mechanisms demonstrated in this study has been provided in
Figure 7.