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In Vivo Nanovector Delivery of a Heart-specific MicroRNA-sponge
Published on: June 15, 2018
Changes in interconnected pathways implicating microRNAs are associated with the activity of apocynin in attenuating
Qinbo Yang1, Jingang Cui1, Peiwei Wang1
1Clinical Research Institute of Integrative Medicine and Yueyang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200437, China.
Abstract:
Myocardial fibrosis is the endpoint pathology common to many cardiovascular disorders. We have previously shown that apocynin (APO), a naturally occurring NADPH oxidase inhibitor, significantly prevents the development of isoproterenol (ISO)-induced myocardial injury and fibrogenesis. The current study investigated the changes in microRNAs (miRNAs) and their potential implication in the cardioprotective effects of APO. Integrative analyses of whole-genome miRNA and gene expression profiles were first performed, revealing that altered expression of miRNAs likely contributed to dysregulated expression of genes associated with multiple interconnected fibrogenic signaling pathways. Importantly, APO treatment exhibited a broad impact on these signaling pathways, which could in part be mediated through miRNA-mediated gene expression regulation. The expression of differentially expressed miRNAs was further validated by real-time PCR analyses. Consistent with the data from miRNA array, compared to that from vehicle-treated normal controls, significantly decreased expression of miR-10b, miR-29c*, miR-30c-1*, miR-30e*, miR-148b, miR-181d, miR-218 and miR-3107* was observed in ISO-challenged vehicle-treated mouse hearts. In contrast, significantly increased expression of these miRNAs was observed in ISO-challenged APO-treated hearts compared to that from ISO-challenged vehicle-treated mice. Moreover, increased expression of miR-21 was observed as a result of ISO administration, which was significantly reduced by APO treatment. Altered protein levels of Col1, TIMP1, Rac2 and gp91(phox) were also validated. Lastly, APO treatment was shown to attenuate pre-established myocardial fibrosis induced by ISO. The results therefore demonstrated for the first time that complex changes in miRNA-mRNA interactome network are associated with the protective effects of APO against ISO-induced myocardial injury and fibrogenesis.
Insights
Apocynin (APO) protects against heart damage by modulating microRNAs (miRNAs) and their associated fibrotic pathways. This study reveals APO
Area of Science:
- Cardiovascular Research
- Molecular Biology
- Pharmacology
Background:
- Myocardial fibrosis is a common outcome in cardiovascular diseases.
- Apocynin (APO), a NADPH oxidase inhibitor, previously demonstrated cardioprotective effects against isoproterenol (ISO)-induced injury.
- The role of microRNAs (miRNAs) in APO's cardioprotective mechanism remained unexplored.
Purpose of the Study:
- To investigate the impact of APO on miRNA expression profiles in ISO-induced myocardial fibrosis.
- To elucidate the potential role of miRNA-mediated gene regulation in APO's cardioprotective effects.
- To identify specific miRNAs involved in the fibrotic response and APO's modulation of these pathways.
Main Methods:
- Integrative analysis of whole-genome miRNA and gene expression profiles in mouse hearts.
- Validation of differentially expressed miRNAs using real-time PCR.
- Assessment of protein level changes for fibrotic markers and NADPH oxidase components.
- Evaluation of APO's efficacy in attenuating pre-established ISO-induced myocardial fibrosis.
Main Results:
- ISO challenge altered the expression of multiple miRNAs, suggesting their involvement in fibrotic signaling pathways.
- APO treatment significantly modulated the expression of these miRNAs, counteracting ISO-induced changes.
- Specific miRNAs (e.g., miR-10b, miR-29c*) were downregulated by ISO and upregulated by APO, while miR-21 showed the opposite pattern.
- APO treatment reduced fibrotic markers (Col1, TIMP1) and NADPH oxidase components (Rac2, gp91(phox)) and attenuated established fibrosis.
Conclusions:
- APO exerts cardioprotective effects against ISO-induced myocardial fibrosis, partly through the modulation of miRNA expression.
- A complex miRNA-mRNA interactome network is associated with APO's protective mechanisms.
- These findings highlight miRNAs as potential therapeutic targets for managing myocardial fibrosis.
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