Soluble (pro)renin receptor as a novel laboratory biomarker of atherosclerosis

Abstract

Atherosclerosis (AS), a chronic inflammatory disease involving the large and middle arteries, is characterized by inflammation, abnormal deposition of lipids, and other pathological events. Endothelial cell injury, the migration and proliferation of vascular smooth muscle cells, and the inflammatory polarization of macrophages play crucial roles in the formation and progression of atherosclerotic plaques. The renin–angiotensin system (RAS), an essential regulator of the inflammatory response, is closely correlated with atherosclerotic plaque formation. Targeting the components of the RAS could be a promising therapeutic strategy for AS. (Pro)renin receptor (PRR), a single transmembrane protein, works as a key regulator of the local RAS with nearly equal affinity to bind to renin and (pro)renin and plays essential roles in cardiovascular homeostasis by targeting multiple RAS-dependent and RAS-independent intracellular signals in cardiovascular cells. sPRR, a soluble form of PRR, is generated by proteases (Furin, a disintegrin and metalloproteinase 19, site-1-protease, or an unknown convertase)-mediated cleavage of the full-length PRR and is released into extracellular spaces, including the plasma and urine, where it participates in various physio-pathological processes. An increasing number of studies have demonstrated an increase in circulating sPRR levels in patients and animals with various cardiovascular diseases, including hypertension and heart failure, which may be promising indicators of these cardiovascular diseases. Amari et al. reported that serum sPRR levels were significantly greater in hemodialysis patients with an ankle–brachial index (ABI) < 0.9 (an indicator of severe AS or obstruction of lower limb arteries) than in patients with an ABI ≥0.9. They reported a negative correlation between serum sPRR levels and ABI independent of other atherogenic risk factors, including age and hemoglobin A1c, suggesting an association between serum sPRR levels and severe AS of the lower limbs. Thus, increased serum sPRR levels may be a marker for AS progression. However, the clinical significance of the sPRR in patients with AS remains unclear. To further determine the association between plasma sPRR levels and the severity of AS, we prospectively enrolled 236 participants in the present study, including 63 subjects with non-AS (n = 63, 58.8 ± 11.7 years) and 173 with AS (n = 173, 67.1 ± 11.0 years, P < 0.001 vs the non-AS group). The diagnosis of subclinical atherosclerosis was established after the carotid intima–media thickness and plaque area were evaluated via bilateral carotid ultrasonography. Patients with heart diseases (rheumatic heart disease, valvular heart disease, and cardiomyopathy), hepatic failure, chronic kidney disease, hyperthyroidism, chronic inflammatory disorders, malignancy, or pulmonary embolism were excluded. The baseline clinical characteristics are shown in Supplementary Table S1. Although plasma brain natriuretic peptide, urea nitrogen, and triglyceride levels were slightly higher in the AS group than in the non-AS group, there were no significant differences in sex, body mass index, comorbidities, blood pressure, parameters reflecting cardiac function, and plasma creatine, uric acid, low-density lipoprotein cholesterol (LDL-c), high density lipoprotein cholesterol (HDL-c), and total cholesterol between the two groups. The ApoE–/– mice were fed with a high-fat diet (HFD) for 16 weeks to establish an atherosclerotic mouse model successfully, which was determined by Oil-red-O staining of the full-length aorta and the aortic root as well as H&E staining of the aortic root (Supplementary Figure S1). The studies involving human participants were reviewed and approved by the Affiliated Hospital of Jiangxi University of Chinese Medicine (JZFYLL20230208002). The patients/participants provided written informed consent to participate in this study. The studies involving animals were reviewed and approved by the Animal Care and Use Committee, which approved the animal protocols at Jiangxi University of Chinese Medicine (No. JZLLSC20230254). The levels of plasma sPRR in AS patients were significantly higher than those in the non-AS groups (15.9 ± 6.9 vs 11.5 ± 4.0 ng/mL, P < 0.001, Figure 1A). After HFD feeding for 16 weeks, the levels of plasma sPRR in ApoE–/– mice were also significantly greater than those in ApoE–/– mice fed with a normal diet (24.1 ± 8.6 vs 10.3 ± 3.1 ng/mL, P < 0.001; Figure 2A). Thus, plasma sPRR levels are significantly elevated under atherosclerotic

1. Introduction

Atherosclerosis (AS), a chronic inflammatory disease involving the large and middle arteries, is characterized by inflammation, abnormal deposition of lipids, and other pathological events. Endothelial cell injury, the migration and proliferation of vascular smooth muscle cells, and the inflammatory polarization of macrophages play crucial roles in the formation and progression of atherosclerotic plaques. The renin–angiotensin system (RAS), an essential regulator of the inflammatory response, is closely correlated with atherosclerotic plaque formation. Targeting the components of the RAS could be a promising therapeutic strategy for AS.

(Pro)renin receptor (PRR), a single transmembrane protein, works as a key regulator of the local RAS with nearly equal affinity to bind to renin and (pro)renin and plays essential roles in cardiovascular homeostasis by targeting multiple RAS-dependent and RAS-independent intracellular signals in cardiovascular cells. sPRR, a soluble form of PRR, is generated by proteases (Furin, a disintegrin and metalloproteinase 19, site-1-protease, or an unknown convertase)-mediated cleavage of the full-length PRR and is released into extracellular spaces, including the plasma and urine, where it participates in various physio-pathological processes. An increasing number of studies have demonstrated an increase in circulating sPRR levels in patients and animals with various cardiovascular diseases, including hypertension and heart failure, which may be promising indicators of these cardiovascular diseases.