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蛋白酶激活受体 2 通过环腺苷酸依赖的蛋白激酶/丝裂原激活蛋白激酶激酶 1/2 依赖性方式控制血管平滑肌细胞增殖。

Protease-Activated Receptor 2 Controls Vascular Smooth Muscle Cell Proliferation in Cyclic AMP-Dependent Protein Kinase/Mitogen-Activated Protein Kinase Kinase 1/2-Dependent Manner.

机构信息

Department of Physiology, Brody School of Medicine, East Carolina University, Greenville, North Carolina, USA.

Edward Via College of Osteopathic Medicine, Carolinas Campus, Spartanburg, South Carolina, USA.

出版信息

J Vasc Res. 2023;60(4):213-226. doi: 10.1159/000532032. Epub 2023 Sep 29.

DOI:10.1159/000532032
PMID:37778342
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10614497/
Abstract

INTRODUCTION

Cardiovascular disorders are characterized by vascular smooth muscle (VSM) transition from a contractile to proliferative state. Protease-activated receptor 2 (PAR2) involvement in this phenotypic conversion remains unclear. We hypothesized that PAR2 controls VSM cell proliferation in phenotype-dependent manner and through specific protein kinases.

METHODS

Rat clonal low (PLo; P3-P6) and high passage (PHi; P10-P15) VSM cells were established as respective models of quiescent and proliferative cells, based on reduced PKG-1 and VASP. Western blotting determined expression of cytoskeletal/contractile proteins, PAR2, and select protein kinases. DNA synthesis and cell proliferation were measured 24-72 h following PAR2 agonism (SLIGRL; 100 nM-10 μm) with/without PKA (PKI; 10 μm), MEK1/2 (PD98059; 10 μm), and PI3K (LY294002; 1 μm) blockade.

RESULTS

PKG-1, VASP, SM22α, calponin, cofilin, and PAR2 were reduced in PHi versus PLo cells. Following PAR2 agonism, DNA synthesis and cell proliferation increased in PLo cells but decreased in PHi cells. Western analyses showed reduced PKA, MEK1/2, and PI3K in PHi versus PLo cells, and kinase blockade revealed PAR2 controls VSM cell proliferation through PKA/MEK1/2.

DISCUSSION

Findings highlight PAR2 and PAR2-driven PKA/MEK1/2 in control of VSM cell growth and provide evidence for continued investigation of PAR2 in VSM pathology.

摘要

简介

心血管疾病的特征是血管平滑肌（VSM）从收缩状态向增殖状态转变。蛋白酶激活受体 2（PAR2）在这种表型转化中的作用尚不清楚。我们假设 PAR2 以依赖于表型的方式通过特定的蛋白激酶控制 VSM 细胞增殖。

方法

根据 PKG-1 和 VASP 的减少，建立大鼠克隆低（PLo；P3-P6）和高传代（PHi；P10-P15）VSM 细胞，作为静止和增殖细胞的相应模型。Western blot 测定细胞骨架/收缩蛋白、PAR2 和选择蛋白激酶的表达。在 PAR2 激动剂（SLIGRL；100 nM-10 μm）作用后 24-72 小时，测量 DNA 合成和细胞增殖，并用 PKA（PKI；10 μm）、MEK1/2（PD98059；10 μm）和 PI3K（LY294002；1 μm）阻断。

结果

PKG-1、VASP、SM22α、钙调蛋白、原肌球蛋白和 PAR2 在 PHi 细胞中低于 PLo 细胞。PAR2 激动后，DNA 合成和细胞增殖在 PLo 细胞中增加，但在 PHi 细胞中减少。Western 分析显示 PHi 细胞中 PKA、MEK1/2 和 PI3K 减少，激酶阻断表明 PAR2 通过 PKA/MEK1/2 控制 VSM 细胞增殖。

讨论

研究结果强调了 PAR2 和 PAR2 驱动的 PKA/MEK1/2 在控制 VSM 细胞生长中的作用，并为进一步研究 PAR2 在 VSM 病理学中的作用提供了依据。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/63c1/10614497/18500d8e0d2b/jvr-2023-0060-0004-532032_F05.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/63c1/10614497/c4897d4f7407/jvr-2023-0060-0004-532032_F01.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/63c1/10614497/34cc318c671c/jvr-2023-0060-0004-532032_F02.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/63c1/10614497/c27f3b5a3bea/jvr-2023-0060-0004-532032_F03.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/63c1/10614497/dd0d3cdb8473/jvr-2023-0060-0004-532032_F04.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/63c1/10614497/18500d8e0d2b/jvr-2023-0060-0004-532032_F05.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/63c1/10614497/c4897d4f7407/jvr-2023-0060-0004-532032_F01.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/63c1/10614497/34cc318c671c/jvr-2023-0060-0004-532032_F02.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/63c1/10614497/c27f3b5a3bea/jvr-2023-0060-0004-532032_F03.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/63c1/10614497/dd0d3cdb8473/jvr-2023-0060-0004-532032_F04.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/63c1/10614497/18500d8e0d2b/jvr-2023-0060-0004-532032_F05.jpg

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