Open AccessChronological attenuation of NPRA / PKG / AMPK signaling promotes vascular aging and elevates blood pressure
Author(s) -
Long Changkun,
Liu Hongfei,
Zhan Wenxing,
Chen Liping,
Yu Zhenping,
Tian Shane,
Xiang Yang,
Chen Shenghan,
Tian XiaoLi
Publication year - 2022
Publication title -
aging cell
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.103
H-Index - 140
eISSN - 1474-9726
pISSN - 1474-9718
DOI - 10.1111/acel.13699
Subject(s) - ampk , enos , biology , senescence , sirtuin 1 , microbiology and biotechnology , amp activated protein kinase , nitric oxide , protein kinase a , gene knockdown , endocrinology , medicine , phosphorylation , nitric oxide synthase , biochemistry , downregulation and upregulation , apoptosis , gene
Hypertension is common in elderly population. We designed to search comprehensively for genes that are chronologically shifted in their expressions and to define their contributions to vascular aging and hypertension. RNA sequencing was conducted to search for senescence‐shifted transcripts in human umbilical vein endothelial cells (HUVECs). Small interfering RNA (siRNA), small‐molecule drugs, CRISPR/Cas9 techniques, and imaging were used to determine genes' function and contributions to age‐related phenotypes of the endothelial cell and blood vessel. Of 25 genes enriched in the term of “regulation of blood pressure,” NPRA was changed most significantly. The decreased NPRA expression was replicated in aortas of aged mice. The knockdown of NPRA promoted HUVEC senescence and it decreased expressions of protein kinase cGMP‐dependent 1 (PKG), sirtuin 1 ( SIRT1 ), and endothelial nitric oxide synthase ( eNOS ). Suppression of NPRA also decreased the phosphorylation of AMP‐activated protein kinase (AMPK) as well as the ratio of oxidized nicotinamide adenine dinucleotide (NAD + )/reduced nicotinamide adenine dinucleotide (NADH) but increased the production of reactive oxygen species (ROS). 8‐Br‐cGMP (analog of cGMP), or AICAR (AMPK activator), counteracted the observed changes in HUVECs. The Npr1 +/− mice presented an elevated systolic blood pressure and their vessels became insensitive to endothelial‐dependent vasodilators. Further, vessels from Npr1 +/− mice increased Cdkn1a but decreased eNos expressions. These phenotypes were rescued by intravenously administrated 8‐Br‐cGMP and viral overexpression of human PKG , respectively. In conclusion, we demonstrate NPRA/PKG/AMPK as a novel and critical signaling axis in the modulation of endothelial cell senescence, vascular aging, and hypertension.