RhoA/ROCK Pathway Activation is Regulated by AT1 Receptor and Participates in Smooth Muscle Migration and Dedifferentiation via Promoting Actin Cytoskeleton Polymerization.

Abstract

BACKGROUND:

In this study, we investigated the mechanism of Rho GTPases signaling on Ang II-mediated cell migration and dedifferentiation in human aortic vascular smooth muscle cells (HA-VSMCs) and an Ang II-infusion mouse model.

METHODS:

Cells were pretreated with different inhibitors or Ang II. Cell migration was detected by Wound healing and Transwell assay. Mice were treated with Ad-RhoA-shRNA virus or Irbesartan or fasudil and then infused with Ang II.

RESULTS:

Ang II treatment induced HA-VSMCs migration in a dose- and time-dependent manner and reduced the expression of VSMC contractile proteins. These effects were significantly suppressed by the inhibition of Ang II type 1 receptor (AT1 receptor), RhoA, and Rho-associated kinase (ROCK). Furthermore, Ang II treatment promoted the activation of RhoA and ROCK, which was reduced by AT1 receptor inhibition. Meanwhile, Ang II treatment induced F-actin polymerization, which was inhibited after ROCK inhibition. In mice, Ang II infusion increased VSMC migration into the neointima and reduced VSMC differentiation proteins levels, and these effects were shown to be dependent on AT1 receptor and RhoA/ROCK pathway.

CONCLUSION:

This study reveals a novel mechanism by which Ang II regulates RhoA/ROCK signaling and actin polymerization via AT1 receptor and then affects VSMC dedifferentiation.

• Authors: Yan Qi, Xiuying Liang, Fan Dai, Haijing Guan, Jingwen Sun, Wenjuan Yao
• Journal: International journal of molecular sciences (Int J Mol Sci) Vol. 21 Issue 15 (Jul 29 2020) ISSN: 1422-0067 [Electronic] Switzerland
• PMID: 32751352 (Publication Type: Journal Article)

Chemical References

• Actins
• Angiotensin II Type 1 Receptor Blockers
• Protein Kinase Inhibitors
• RNA, Small Interfering
• Receptor, Angiotensin, Type 1
• Vasodilator Agents
• Angiotensin II
• RHOA protein, human
• 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine
• rho-Associated Kinases
• rhoA GTP-Binding Protein
• Irbesartan
• fasudil

Topics

• 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine (analogs & derivatives, pharmacology)
• Actin Cytoskeleton (drug effects, genetics, metabolism)
• Actins (genetics, metabolism)
• Angiotensin II (pharmacology)
• Angiotensin II Type 1 Receptor Blockers (pharmacology)
• Animals
• Cell Dedifferentiation (drug effects)
• Cell Line
• Cell Movement (drug effects)
• Gene Expression Regulation
• Humans
• Irbesartan (pharmacology)
• Male
• Mice
• Mice, Inbred C57BL
• Muscle, Smooth, Vascular (cytology, drug effects, metabolism)
• Myocytes, Smooth Muscle (cytology, drug effects, metabolism)
• Polymerization (drug effects)
• Protein Kinase Inhibitors (pharmacology)
• RNA, Small Interfering (genetics, metabolism)
• Receptor, Angiotensin, Type 1 (genetics, metabolism)
• Signal Transduction
• Vasodilator Agents (pharmacology)
• rho-Associated Kinases (genetics, metabolism)
• rhoA GTP-Binding Protein (antagonists & inhibitors, genetics, metabolism)