Rare SNP rs12731181 in the miR-590-3p Target Site of the Prostaglandin F _2α Receptor Gene Confers Risk for Essential Hypertension in the Han Chinese Population

Abstract

P rostanoids are biologically active derivatives of arachidonic acid that is released from membrane phospholipids and then converted through cyclooxygenase metabolism. These lipid mediators play an important role in blood pressure (BP) homeostasis. Both traditional nonsteroidal anti-inflammatory drugs and cyclooxygenase-2 selective nonsteroidal antiinflammatory drugs can elevate BP in patients. 1 Vasodilator prostanoids, such as prostaglandin (PG) I 2 and PGE 2 , are essential for regulating renal blood flow and mediating salt/ water reabsorption in the kidney.2,3 Deletion of the PGI 2 receptor or the PGE 2 receptor subtype 2 (EP2) results in saltsensitive hypertension. 4,5 However, inactivation of the PGE 2 receptor subtypes 1 and 3 (EP1 and EP3, respectively) reduces chronic angiotensin-II-driven hypertension and attenuates the angiotensin-II pressor response by reducing arterial contractility. 6,7 The levels of PGF 2α , a vasoconstrictor, are augmented © 2015 American Heart Association, Inc. Objective-To investigate whether rs12731181 (A→G) interrupted miR-590-3p-mediated suppression of the prostaglandin F 2α receptor (FP) and whether it is associated with essential hypertension in the Chinese population. Approach and Results-We found that miR-590-3p regulates human FP gene expression by binding to its 3′-untranslated region. rs12731181 (A→G) altered the binding affinity between miR-590-3p and its FP 3′-untranslated region target, thus reducing the suppression of FP expression, which, in turn, enhanced FP receptor-mediated contractility of vascular smooth muscle cells. Overexpression of FP augmented vascular tone and elevated blood pressure in mice. An association study was performed to analyze the relationship between the FP gene and essential hypertension in the Han Chinese population. The results indicated that the rs12731181 G allele was associated with susceptibility to essential hypertension. Carriers of the AG genotype exhibited significantly higher blood pressure than those of the AA genotype. FP gene expression was significantly higher in human peripheral leukocytes from individuals with the AG genotype than that in leukocytes from individuals with the AA genotype. Conclusions-rs12731181 in the seed region of the miR-590-3p target site is associated with increased risk of essential hypertension and represents a new paradigm for FP involvement in blood pressure regulation. in circulation under the conditions that increase cardiovascular risks, for example, after chronic high-salt intake, smoking, and hypercholesterolemia. 8 The PGF 2α receptor (FP) is highly expressed in distal convoluted tubules and cortical collecting ducts in the kidney and mediates water absorption.9 FP is also present in resistance arterioles that are involved in regulating the vasopressor response.8 Thus, ablation of FP induces hypotension and retards atherosclerosis in low-density lipoprotein receptor-knockout mice. 10MicroRNAs (miRNAs), ≈22 single-stranded nucleotide RNA molecules, play an important gene-regulatory function mo...

Mechanisms of Vascular Smooth Muscle Contraction and the Basis for Pharmacologic Treatment of Smooth Muscle Disorders

“…These miRs are all important regulators of VSMC phenotype plasticity. A further study in a Chinese population identified the SNP rs12731181 (A to G) in the prostaglandin F 2 α receptor that was more prevalent in hypertensive individuals ( Xiao et al, 2015 ). This polymorphism reduces the likelihood of miR-590-3p binding, thus increasing prostaglandin F 2 α receptor expression and enhancing prostaglandin-mediated contractility of VSMCs ( Xiao et al, 2015 ).…”

Prostaglandin F2α Facilitates Hepatic Glucose Production Through CaMKIIγ/p38/FOXO1 Signaling Pathway in Fasting and Obesity

“…Human FP (hFP) hepatocyte transgenic (HCTG) and nontransgenic (NTG) littermates were obtained from the mating of Tg-hFP-STOP Flox (16) and Alb Cre mice. FP exon2-floxed mice (FP F/F ) were generated through CRISPR/Cas9 technology by Shanghai Biomodel Organism Science & Technology Development Co., Ltd. (Shanghai, People's Republic of China) and crossed with Alb Cre mice to obtain hepatic FP-deficient mice (FP F/F Alb cre ).…”

Modeling microRNA-driven post-transcriptional regulation by using exon-intron split analysis (EISA) in pigs

“…Other genes showing significant post-transcriptional regulation were the following: The sterile α motif domain containing 4A ( SAMD4A ) that has been linked to the inhibition of preadipocyte differentiation and leanness phenotype in knockdown experiments [84,85]. The prostaglandin F2-receptor protein (PTGFR), for which overexpression has been associated with hypertension and obesity risk [86], and its repression appears to improve insulin sensitivity and glucose homeostasis [87]. The expression of serpin E1 and E2 ( SERPINE1 , SERPINE2 ) is linked to obesogenic states and diabetic symptoms [88], while their inhibition improved glucose metabolism [89].…”