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P38 MAPK Signaling Pathway Mediates Angiotensin II-Induced miR143/145 Gene Cluster Downregulation during Aortic
Bowen Li1, Zhiwei Wang1, Zhipeng Hu1
1Department of Cardiovascular Surgery, Renmin Hospital of Wuhan University, Wuhan, Hubei Province, People's Republic of China.
Background:
We endeavored to prove that angiotensin II (Ang II) regulates both the expression of micro-RNA143/145 (miR143/145) and differentiation of vascular smooth muscle cells (VSMCs) during the formation of aortic dissection (AD). We also studied the contribution of p38 mitogen-activated protein kinase (MAPK) signaling pathway toward this process.
Methods:
Ascending aortic tissues were harvested from the patients with AD and organ donors. Tissues were immunostained with labeled antibodies targeting p38 MAPK, phospho-p38 MAPK, alpha-smooth muscle actin (α-SMA), and osteopontin (OPN). Next, we treated mouse aortic VSMCs with different regimens of Ang II (duration and dosages) in vitro and determined expression levels of miR143/145 and VSMC phenotype marker proteins (α-SMA and OPN) by quantitative polymerase chain reaction and/or western blotting. SB203580 was used to inhibit the p38 MAPK signaling pathway. Finally, the VSMC phenotype was validated by immunofluorescence microscopy.
Results:
Expression of phospho-p38 MAPK was significantly greater in the AD tissue. Ang II induced the phenotypic switching of VSMCs along with the downregulation of an miR143/145 gene cluster. Expression of OPN and phospho-p38 was significantly increased in VSMCs treated with 0.1 μM Ang II for 12 hr. Furthermore, the expression of miR143 and miR145 was downregulated by Ang II treatment. When the p38 MAPK signaling pathway was blocked by pretreatment with an SB203580 inhibitor, the expression of miR143, miR145, and VSMC phenotypic markers was not affected by Ang II. Immunohistochemical staining of aortic tissues donated by AD patients and healthy donors showed that the expression of α-SMA decreased in pathological tissue, while the OPN increased and the arrangement of the smooth muscle cells of the media was dysregulated, which we verified in vitro.
Conclusions:
Ang II could regulate the expression of miR143/145 gene cluster and the phenotypic switching of VSMCs via the p38 MAPK signaling pathway. This may play an important role in the pathogenesis of AD.
Insights
Angiotensin II (Ang II) regulates microRNA-143/145 (miR143/145) and vascular smooth muscle cell (VSMC) differentiation via the p38 MAPK pathway, impacting aortic dissection (AD) development.
Area of Science:
- Cardiovascular Biology
- Molecular Biology
- Cell Biology
Background:
- Aortic dissection (AD) involves complex molecular mechanisms.
- Vascular smooth muscle cell (VSMC) differentiation is crucial in maintaining aortic integrity.
Purpose of the Study:
- To investigate the role of Angiotensin II (Ang II) in regulating micro-RNA 143/145 (miR143/145) expression.
- To determine the impact of Ang II on VSMC differentiation during AD.
- To elucidate the involvement of the p38 mitogen-activated protein kinase (MAPK) signaling pathway.
Main Methods:
- Analysis of aortic tissues from AD patients and organ donors.
- Immunohistochemical staining for p38 MAPK, phospho-p38 MAPK, α-SMA, and OPN.
- In vitro treatment of mouse aortic VSMCs with Ang II.
- Quantitative PCR and Western blotting to assess miR143/145 and VSMC marker expression.
- Inhibition of the p38 MAPK pathway using SB203580.
Main Results:
- Phospho-p38 MAPK expression was elevated in AD tissues.
- Ang II induced VSMC phenotypic switching and downregulated miR143/145.
- Ang II treatment increased OPN and phospho-p38 expression in VSMCs.
- Inhibition of p38 MAPK blocked Ang II-induced changes in miR143/145 and VSMC markers.
- AD tissues showed decreased α-SMA, increased OPN, and dysregulated VSMC arrangement.
Conclusions:
- Ang II regulates miR143/145 expression and VSMC phenotypic switching through the p38 MAPK pathway.
- This mechanism is implicated in the pathogenesis of aortic dissection.
- Targeting this pathway could offer therapeutic strategies for AD.
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