Chronological attenuation of NPRA/PKG/AMPK signaling promotes vascular aging and elevates blood pressure

• Published in: Aging cell 2022-09, Vol.21 (9), p.e13699-n/a
• Main Authors: Long, Changkun, Liu, Hongfei, Zhan, Wenxing, Chen, Liping, Yu, Zhenping, Tian, Shane, Xiang, Yang, Chen, Shenghan, Tian, Xiao‐Li
• Format: Article
• Language: English
• Subjects: Aged; Aging; AMP-Activated Protein Kinases - metabolism; AMPK; Animals; Atherosclerosis; Blood Pressure; Blood vessels; Cell cycle; Cells, Cultured; Coronary vessels; CRISPR; Cyclic GMP; Cyclic GMP - analogs & derivatives; Cyclin-dependent kinases; Cytokines; endothelial cell; Endothelial cells; Endothelium; Enzymes; Genes; Geriatrics; Human Umbilical Vein Endothelial Cells - metabolism; Humans; Hypertension; Hypertension - genetics; Hypertension - metabolism; Kinases; Mice; NAD; NAD - metabolism; Nitric oxide; Nitric Oxide - metabolism; Nitric Oxide Synthase Type III - metabolism; Nitric-oxide synthase; NPRA; Peptides; Phenotypes; Phosphorylation; PKG; Protein kinase C; Proteins; Reactive oxygen species; RNA, Small Interfering - metabolism; Senescence; siRNA; SIRT1 protein; Statistical analysis; Thionucleotides; Umbilical vein
• ISSN: 1474-9718; 1474-9726
• DOI: 10.1111/acel.13699

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. Natriuretic peptide receptor A (NPRA) is chronologically decreased in senescent endothelial cell and aged vessels. The decrease in NPRA expression promotes endothelial cell senescence, vascular aging, and hypertension through NPRA/PKG/AMPK signaling axis in both endothelial cell and engineered animal models.