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MiR-29b as a therapeutic agent for angiotensin II-induced cardiac fibrosis by targeting TGF-?/Smad3 signaling.

ABSTRACT: Loss of miR-29 is associated with cardiac fibrosis. This study examined the role and therapeutic potential of miR-29 in mouse model of hypertension induced by angiotensin II (AngII). By using microRNA microarray, in situ hybridization, and real-time polymerase chain reaction, we found that AngII-induced cardiac fibrosis in the hypertensive heart and in cultured cardiac fibroblasts were associated with downregulation of miR-29a-c via a Smad3-dependent mechanism. In vitro knockdown of miR-29b enhanced but overexpression of miR-29b inhibited AngII-induced fibrosis, revealing a protective role of miR-29b in cardiac fibrosis in response to AngII. This was further demonstrated in vivo by the ability of overexpressing miR-29b in the mouse heart to prevent AngII-mediated cardiac fibrosis and cardiac dysfunction. Importantly, we also found that restored miR-29b in the established hypertensive heart was capable of blocking progressive cardiac fibrosis and improving cardiac dysfunction, demonstrating a therapeutic potential of miR-29b for chronic heart disease. Further studies revealed that targeting the transforming growth factor (TGF)-?1 coding sequence region, thereby inhibiting TGF-?/Smad3 signaling, could be a new mechanism by which miR-29b inhibited AngII-induced cardiac fibrosis. In conclusion, miR-29b plays a protective role in AngII-mediated cardiac remodeling and may be a therapeutic agent for cardiac fibrosis by targeting the TGF-?/Smad3 pathway.

SUBMITTER: Zhang Y

PROVIDER: S-EPMC4015231 | biostudies-literature | 2014 May

REPOSITORIES: biostudies-literature

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miR-29b as a therapeutic agent for angiotensin II-induced cardiac fibrosis by targeting TGF-β/Smad3 signaling.

Zhang Yang Y Huang Xiao-Ru XR Wei Li-Hua LH Chung Arthur Ck AC Yu Cheuk-Man CM Lan Hui-Yao HY

Molecular therapy : the journal of the American Society of Gene Therapy 20140226 5

Loss of miR-29 is associated with cardiac fibrosis. This study examined the role and therapeutic potential of miR-29 in mouse model of hypertension induced by angiotensin II (AngII). By using microRNA microarray, in situ hybridization, and real-time polymerase chain reaction, we found that AngII-induced cardiac fibrosis in the hypertensive heart and in cultured cardiac fibroblasts were associated with downregulation of miR-29a-c via a Smad3-dependent mechanism. In vitro knockdown of miR-29b enha ...[more]

PMID: 24569834

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Project description:Aberrant activation of angiotensin II (Ang II) accelerates hypertensive heart failure (HF); this has drawn worldwide attention. The complex Ang II/transforming growth factor (TGF)-β1 networking consists of central mechanisms underlying pro-fibrotic effects; however, this networking still remains unclear. Cellular communication network 5 (CCN5), known as secreted matricellular protein, mediates anti-fibrotic activity by inhibiting fibroblast-to-myofibroblast transition and the TGF-β1 signaling pathway. We hypothesized that endogenous CCN5 plays an essential role in TGF-β1/Ang II networking-induced cardiac fibrosis (CF), which accelerates the development of hypertensive HF. This study aimed to investigate the potential role of CCN5 in TGF-β1/Ang II networking-induced CF. Our clinical retrospective study demonstrated that serum CCN5 decreased in hypertensive patients, but significantly increased in hypertensive patients taking oral angiotensin-converting enzyme inhibitor (ACEI). A negative association was observed between CCN5 and Ang II in grade 2and 3 hypertensive patients receiving ACEI treatment. We further created an experimental model of high Ang II-induced hypertensive HF. CCN5 was downregulated in the spontaneously hypertensive rats (SHRs) and increased via the inhibition of Ang II production by ACEI. This CCN5 downregulation may activate the TGF-β1 signaling pathway, which promotes direct deposition of the extracellular matrix (ECM) and fibroblast-to-myofibroblast transition via activated Smad-3. Double immunofluorescence staining of CCN5 and cell markers of cardiac tissue cell types suggested that CCN5 was mainly expressed in the cardiac fibroblasts. Isolated cardiac fibroblasts were exposed to Ang II and transfected with small interfering RNA targeting CCN5. The expression of TGF-β1 together with Col Ia and Col IIIa was further promoted, and alpha-smooth muscle actin (α-SMA) was strongly expressed in the cardiac fibroblasts stimulated with Ang II and siRNA. In our study, we confirmed the anti-fibrotic ability of endogenous CCN5 in high Ang II-induced hypertensive HF. Elevated Ang II levels may decrease CCN5 expression, which subsequently activates TGF-β1 and finally promotes the direct deposition of the ECM and fibroblast-to-myofibroblast transition via Smad-3 activation. CCN5 may serve as a potential biomarker for estimating CF in hypertensive patients. A novel therapeutic target should be developed for stimulating endogenous CCN5 production.

Dataset Information

MiR-29b as a therapeutic agent for angiotensin II-induced cardiac fibrosis by targeting TGF-?/Smad3 signaling.

Publications

miR-29b as a therapeutic agent for angiotensin II-induced cardiac fibrosis by targeting TGF-β/Smad3 signaling.

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