Regulation mechanism of AT1R/miR-26a pathway in hypertensive vascular remodeling

Wenqian ZHANG; Qiaozhu WANG; Peifei SHI; Yanjing FENG; Dengfeng GAO; Xin LIU

doi:10.16016/j.1000-5404.201907236

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Regulation mechanism of AT1R/miR-26a pathway in hypertensive vascular remodeling

Basic Medicine | 更新时间：2026-01-09

- Regulation mechanism of AT1R/miR-26a pathway in hypertensive vascular remodeling
- Journal of Third Military Medical University Vol. 42, Issue 1, Pages: 59-66(2020)
- 作者机构：
  
  710004 西安，西安交通大学第二附属医院心内科
- 作者简介：
- 基金信息：
  
  the General Program of National Natural Science Foundation of China(81570382);the General Program of National Natural Science Foundation of China(81872563)
- DOI：10.16016/j.1000-5404.201907236
  CLC： R544.1;R966;R977.6
- Received：30 July 2019，
  
  Revised：2019-10-18，
  
  Published：15 January 2020
- 稿件说明：
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Wenqian ZHANG, Qiaozhu WANG, Peifei SHI, et al. Regulation mechanism of AT1R/miR-26a pathway in hypertensive vascular remodeling[J]. Journal of Third Military Medical University, 2020, 42(1): 59-66.
DOI：

Wenqian ZHANG, Qiaozhu WANG, Peifei SHI, et al. Regulation mechanism of AT1R/miR-26a pathway in hypertensive vascular remodeling[J]. Journal of Third Military Medical University, 2020, 42(1): 59-66. DOI： 10.16016/j.1000-5404.201907236.

摘要

目的

阐明AT1R/miR-26a通路在高血压血管重塑中的重要作用及分子机制。

方法

① 将24只8周龄雄性自发性高血压大鼠(SHRs)分为(

=8)：氯沙坦干预组[氯沙坦20 mg/(kg·d)灌胃

]

、哌唑嗪干预组[哌唑嗪5 mg/(kg·d)灌胃

]

、SHR模型对照组[纯水10 mL/(kg·d)灌胃

]

；雄性WKY大鼠作为正常对照组[纯水10 mL/(kg·d)灌胃

]

(

=6)，干预8周；干预前后3~5 d测定鼠尾动脉收缩压(SBP)，直至干预期满。②将各组大鼠麻醉取胸主动脉，qPCR检测大鼠胸主动脉miR-26a的表达水平。③剩余组织石蜡包埋行HE、Masson染色，α-actin和PCNA免疫组化染色。④Western blot检测大鼠胸主动脉AT1R、TGFβ1、p-smad3、CTGF表达情况。⑤将培养传至3~9代的大鼠胸主动脉平滑肌细胞(VSMC)分为AngⅡ处理组(VSMC+AngⅡ，AngⅡ10

-7

mol/L，作用24 h处理细胞)和对照组(VSMC+ Ctrl)(

=6)，qPCR检测miR-26a的表达水平，Western blot检测smad3和p-smad3表达情况。

结果

① 干预期满时，氯沙坦组、哌唑嗪组SBP明显低于模型对照组，但均高于正常对照组(

0.05)，氯沙坦组、哌唑嗪组间SBP差异无统计学意义(

0.05)。②氯沙坦组、哌唑嗪组胸主动脉miR-26a相对表达高于模型对照组(

0.05)，且氯沙坦组高于哌唑嗪组(

0.05)，但均较正常对照组表达低(

0.05)。③氯沙坦组、哌唑嗪组中膜厚度/管腔内经(MT/LD)、胶原体积分数(CVF)及平滑肌细胞增值指数均低于模型对照组(

0.05)，且氯沙坦组低于哌唑嗪组；正常对照组血管管壁未见明显增厚，平滑肌分布均匀且动脉内膜完整，无显著的胶原纤维沉积现象，平滑肌细胞排列整齐，胞核形态规则。④氯沙坦组、哌唑嗪组胸主动脉AT1R、p-smad3、TGFβ1、CTGF相对表达低于

模型对照组(

0.05)，且氯沙坦组低于哌唑嗪组(

0.05)，但均高于正常对照组(

0.05)。⑤VSMC+AngⅡ组细胞miR-26a表达显著低于对照组，且p-smad3表达显著高于VSMC+Ctrl组(

0.05)。

结论

miR-26a可阻止血压升高，且在高血压血管重塑进程中具有保护性作用；阻断AT1受体可通过上调miR-26a改善高血压血管重塑。

Abstract

Objective

To elucidate the important role and molecular mechanism of AT1R/miR-26a pathway in hypertensive vascular remodeling.

Methods

① Eight-week-old male spontaneously hypertensive rats (SHRs) were randomly divided into losartan group [gavage with losartan 20 mg/(kg·d) for 8 weeks

]

prazosin group [gavage with prazosin 5 mg/(kg·d) for 8 weeks

]

SHR control group [gavage with pure water 10 mL/(kg·d) for 8 weeks

]

with 8 animals in each groups. Six eight-week-old male WKY rats served as normal control group [gavage with pure water 10 mL/(kg·d) for 8 weeks

]

. All rats in each group were measured for systolic blood pressure (SBP) through tail artery in 3 to 5 d before and during the intervention period until the end of treatment. ② After the rats were anesthetized

the thoracic aorta were harvested for detecting the expression level of miR-26a by real-time quantitative polymerase chain reaction (qPCR). ③ The thoracic aorta was embedded in paraffin

and sectioned for HE and Masson staining

α-actin and PCNA immunohistochemistry. ④ The expression of AT1R

TGFβ1

p-smad3 and CTGF in the thoracic aorta were detected by Western blotting. ⑤ The rat thoracic aortic smooth muscle cells (VSMCs) at 3 to 9 passages were divided into AngⅡ treatment group (VSMCs+AngⅡ

AngⅡ10

-7

mol/L

treated for 24 h)

and control group (VSMC+Ctrl). qPCR was used to detect the expression level of miR-26a

and the expression of smad3 and p-smad3 was observed by Western blotting.

Results

① At the end of treatment received

SBP was significantly lower in the losartan an

d prazosin groups than the SHR control group

but all of them were obviously higher than that of normal control group (

0.05). There was no significant difference in SBP between the losartan and prazosin groups (

0.05). ②The expression of miR-26a in the thoracic aorta was notably higher in the losartan and prazosin groups than the SHR control group

but statistically lower than the normal control group (

0.05)

and that of the losartan group was higher than that of the prazosin group (

0.05). ③ Media thickness/lumen diameter (MT/LD)

collagen volume fraction (CVF)

and smooth muscle cell proliferation index in the losartan and prazosin groups were remarkably lower than those in the SHR control group (

0.05)

and those in the losartan group were lower than those of the prazosin group. The normal control group had no obvious thickening of the vascular wall

with well-arranged smooth muscle cells

and regular morphology of the nucleus

and no significant collagen fiber deposition. ④The expression levels of AT1R

p-smad3

TGFβ1 and CTGF in the thoracic aorta were significantly lower in the losartan and prazosin groups than the SHR control group (

0.05). Although those in the losartan group were lower than those of the prazosin group (

0.05)

the levels in the both group were higher than those of normal control group (

0.05). ⑤The expression of miR-26a was significantly lower

and that of p-smad3 was higher in VSMC+AngⅡ group when compared with VSMC+Ctrl group (

0.05).

Conclusion

miR-26a prevents blood pressure from rising and has a protective effect in the process of hypertensive vascular remodeling. Blocking AT1 receptor may improve the remodeling by up-regulating miR-26a.

关键词

Keywords

references

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