P300/Sp1-Mediated High Expression of p16 Promotes Endothelial Progenitor Cell Senescence Leading to the Occurrence of Chronic Obstructive Pulmonary Disease

Zhihui He,Min Gao,Xuefeng Zhang,Huaihuai Peng,Menghao Zeng,Guibin Liang,Xin Zong

doi:10.1155/2021/5599364

Abstract

Objective Chronic obstructive pulmonary disease (COPD) is a common chronic disease and develops rapidly into a grave public health problem worldwide. However, what exactly causes the occurrence of COPD remains largely unclear. Here, we are trying to explore whether the high expression of p16 mediated by p300/Sp1 can cause chronic obstructive pulmonary disease through promoting the senescence of endothelial progenitor cells (EPCs). Methods Peripheral blood EPCs were isolated from nonsmoking non-COPD, smoking non-COPD, and smoking COPD patients. The expressions of p16, p300, and senescence-related genes were detected by RT-PCR and Western Blot. Then, we knocked down or overexpressed Sp1 and p300 and used the ChIP assay to detect the histone H4 acetylation level in the promoter region of p16, CCK8 to detect cell proliferation, flow cytometry to detect the cell cycle, and β-galactosidase staining to count the proportion of senescent cells. Results The high expression of p16 was found in peripheral blood EPCs of COPD patients; the cigarette smoke extract (CSE) led to the increase of p16. The high expression of p16 in EPCs promoted cell cycle arrest and apoptosis. The CSE-mediated high expression of p16 promoted cell senescence. The expression of p300 was increased in peripheral blood EPCs of COPD patients. Moreover, p300/Sp1 enhanced the histone H4 acetylation level in the promoter region of p16, thereby mediating the senescence of EPCs. And knockdown of p300/Sp1 could rescue CSE-mediated cell senescence. Conclusion p300/Sp1 enhanced the histone H4 acetylation level in the p16 promoter region to mediate the senescence of EPCs.

Highlights

Chronic obstructive pulmonary disease (COPD) is a common chronic disease whose prevalence, disability rate, mortality rate, and social burden caused by it have been increasing year by year, developing into a severe public health issue
We detected the expression of p16 in different groups by RT-PCR and Western Blot, whose results showed that the mRNA and protein levels of p16 were significantly increased in peripheral blood endothelial progenitor cells (EPCs) of COPD patients (Figures 1(b) and 1(c))
We knocked down p16 in cigarette smoke extract (CSE)-treated non-COPD EPC cells, and we found that knocking down p16 could inhibit the G1/S phase arrest caused by CSE (Figure 2(f))

Summary

Introduction

Chronic obstructive pulmonary disease (COPD) is a common chronic disease whose prevalence, disability rate, mortality rate, and social burden caused by it have been increasing year by year, developing into a severe public health issue. EPCs are precursor cells of endothelial cells, which are differentiated from mesoderm angioblasts and participate in human embryonic angiogenesis [5, 6]. Due to their differentiation into endothelial cells and their biological characteristics such as secretion of vasoactive substances, proliferation, homing, and migration, endothelial progenitor cells (EPCs) play a very important role in postnatal angiogenesis, reendothelialization, tissue regeneration, and repair [7,8,9]. P16 is the second most common tumor suppressor gene just after p53 It has been widely considered a familial melanoma gene, whose immunohistochemistry has a clearly defined role in certain pathological conditions [11].

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Results

Conclusion