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

Abstract

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.

Biomarkers of aging

“…Their activity declines in VECs and VSMCs during aging, and their overexpression counteracts vascular aging (Grootaert and Bennett, 2022). Furthermore, with cutting-edge technologies, a series of molecules have been found to be associated with or functionally contribute to vascular aging, including hypoxia-inducible factor-1α (HIF-1α), vascular endothelial growth factor (VEGF), Klotho, FOXO1A, FOXO3A, adrenoceptor beta 2 (ADRB2), milk fat globule epidermal growth factor 8 (MFG-E8), natriuretic peptide receptor A (NPRA), and APOE (Cai et al, 2022d;Long et al, 2022;Wang et al, 2021c;Zhang et al, 2020e).…”

Predicting lifespan-extending chemical compounds for C. elegans with machine learning and biologically interpretable features

“…One recent study, however, found two antihypertensive medications to extend longevity in C. elegans [ 50 ]. Furthermore, in recent in vivo experiments with Npr1 knockout mice, Npr1 +/– mice has exhibited vascular aging [ 51 ]. As recorded in DrugBank, Flavin adenine dinucleotide (FAD) is a coenzyme form of vitamin B2 used in clinical conditions associated with vitamin B2 deficiency.…”

Acupuncture therapy for isolated ischemic oculomotor nerve palsy: A case report

“…[1,8] Long-term hypertension in the patient’s history has accelerated endothelial cell aging and vascular aging, altered vascular hemodynamics, and predisposed the patient to microvascular ischemia. [9,10] Microvascular ischemia leads to the release of high mobility group box 1 by neurons, reactive microglia, and reactive astrocytes. [11] High mobility group box 1 stimulates microglial polarization and the formation of pro-inflammatory M1-type cells, which causes neuroinflammation in ischemic areas.…”