Atrial Natriuretic Peptide Inhibited ABCA1/G1-dependent Cholesterol Efflux Related to Low HDL-C in Hypertensive Pregnant Patients.

Yubing Dong,Wanyu Liu,Yi Lin,Wei Song,Yinong Jiang,Wei Zhang

doi:10.3389/fphar.2021.715302

Abstract

Objective: It has been reported that atrial natriuretic peptide (ANP) regulates lipid metabolism by stimulating adipocyte browning, lipolysis, and lipid oxidation, and by impacting the secretion of adipokines. In our previous study, we found that the plasma ANP concentration of hypertensive disorders of pregnancy (HDP) was significantly increased in comparison to that of normotensive pregnancy patients. Thus, this study’s objective was to investigate the lipid profile in patients with HDP and determine the effects of ANP on the cholesterol efflux in THP-1 macrophages.Methods: A total of 265 HDP patients and 178 normotensive women as the control group were recruited. Clinical demographic characteristics and laboratory profile data were collected. Plasma total triglycerides (TGs), total cholesterol (TC), low-density cholesterol (LDL-C), and high-density cholesterol (HDL-C) were compared between the two groups. THP-1 monocytes were incubated with different concentrations of ANP. ATP-binding cassette transporter A1 (ABCA1) and ATP-binding cassette transporter G1 (ABCG1) mRNA and protein were evaluated. ABCA1- and ABCG1-mediated cholesterol efflux to apolipoprotein A-Ⅰ (apoA-Ⅰ) and HDL, respectively, were measured by green fluorescent labeled NBD cholesterol. Natriuretic peptide receptor A (NPR-A) siRNA and specific agonists of the peroxisome proliferator–activated receptor-γ (PPAR-γ) and liver X receptor α (LXRα) were studied to investigate the mechanism involved.Results: Plasma TG, TC, LDL-C, and LDL-C/HDL-C were significantly increased, and HDL-C was significantly decreased in the HDP group in comparison to the control (all p < 0.001). ANP inhibited the expression of ABCA1 and ABCG1 at both the mRNA and protein levels in a dose-dependent manner. The functions of ABCA1- and ABCG1-mediated cholesterol efflux to apoA-I and HDL were significantly decreased. NPR-A siRNA further confirmed that ANP binding to its receptor inhibited ABCA1/G1 expression through the PPAR-γ/LXRα pathway.Conclusions: ABCA1/G1 was inhibited by the stimulation of ANP when combined with NPR-A through the PPAR-γ/LXRα pathway in THP-1 macrophages. The ABCA1/G1-mediated cholesterol efflux was also impaired by the stimulation of ANP. This may provide a new explanation for the decreased level of HDL-C in HDP patients.

Highlights

Hypertensive disorders of pregnancy (HDP) is one of the leading causes of placental abruption, stroke, multiple organ failure, disseminated intravascular coagulation, intrauterine growth retardation, and intrauterine death (Anonymous, 2020)
Turgay Emet et al found that plasma total cholesterol (TC), triglyceride (TG), and lowdensity lipoprotein cholesterol (LDL-C) levels were significantly increased as pregnancy progressed (Emet et al, 2013)
We inhibited Natriuretic peptide receptor-A (NPR-A) by small interfering RNA (siRNA) and found that both the PPARγ agonist and the Liver X receptor α (LXRα) agonist abolished the inhibition of ABCA1 and ABCG1 induced by Atrial natriuretic peptide (ANP) (Figures 4E–H, lane 7 and lane 8). These results demonstrated that ABCA1 and ABCG1 were inhibited by ANP when combined with NPR-A through the PPARγ/LXRα pathway

Summary

Introduction

Hypertensive disorders of pregnancy (HDP) is one of the leading causes of placental abruption, stroke, multiple organ failure, disseminated intravascular coagulation, intrauterine growth retardation, and intrauterine death (Anonymous, 2020). Turgay Emet et al found that plasma total cholesterol (TC), triglyceride (TG), and lowdensity lipoprotein cholesterol (LDL-C) levels were significantly increased as pregnancy progressed (Emet et al, 2013). Pro-ANP was hydrolyzed by serine protease corin and released the same amount of N-terminal pro-atrial natriuretic peptide (NT-pro-ANP) and ANP when the blood pressure and volume increased (Nakagawa et al, 2019). Natriuretic peptide receptor-C acts as a clearance receptor when binding with ANP. NPR-A knockout caused hypertension in mice (Oliver et al, 1997), indicating that ANP binding to NPR-A plays an important role in the regulation of blood pressure. Our previous study showed that the plasma NT–pro-ANP level was significantly increased in HDP patients (Lin et al, 2021)

Methods

Results

Conclusion