Molecular mechanism of lysophosphatidic acid-induced hypertensive response.

Kuniyuki Kano,Satoshi Ishii,Hiroshi Yukiura,Asuka Inoue,Junken Aoki,Takao Shimizu,Hirotaka Matsumoto,Jerold Chun,Motomu Kanai

doi:10.1038/s41598-019-39041-4

Abstract

Lysophosphatidic acid (LPA) is a blood-derived bioactive lipid with numerous biological activities exerted mainly through six defined G protein-coupled receptors (LPA1-LPA6). LPA was first identified as a vasoactive compound because it induced transient hypertension when injected intravenously in rodents. Here, we examined the molecular mechanism underlying the LPA-induced hypertensive response. The LPA-induced hypertensive response was significantly attenuated by pretreatment with a Rho kinase inhibitor, which blocks Gα12/13 signaling. Consistent with this, the response was weakened in KO mice of LPA4, a Gα12/13-coupling LPA receptor. KO mice of another Gα12/13-coupling LPA receptor, LPA6, also showed an attenuated LPA-induced hypertensive response. However, LPA6 KO mice also displayed attenuated pressor responses to an adrenergic agent and abnormal blood vessel formation. Using several LPA analogs with varied affinity for each LPA receptor, we found a good correlation between the hypertensive and LPA4 agonistic activities. Incubated mouse plasma, which contained abundant LPA, also induced a hypertensive response. Interestingly the response was completely abolished when the plasma was incubated in the presence of an ATX inhibitor. Together, these results indicate that circulating LPA produced by ATX contributes to the elevation of blood pressure through multiple LPA receptors, mainly LPA4.

Highlights

Lysophosphatidic acid (LPA: 1- or 2-acyl-sn-glycerol-3-phosphate) is a bioactive lipid that can induce a number of cellular responses, including cell proliferation, migration and cytoskeletal reorganization, most of which are mediated through six defined G-protein-coupled receptors (GPCRs) specific to LPA1,2
To clarify the molecular mechanism underlying the LPA-induced pressor response, we examined whether the LPA receptors cloned so far (LPA1–6) are involved in LPA-induced transient hypertension by utilizing a combination of LPA receptor KO mice and LPA analogs
As was demonstrated in other experimental animals, administration of LPA (18:1-LPA, 1.4 mg/kg, i.v.) in ICR mice produced a weak hypotension followed by a transient hypertension that lasted for a minute (Fig. 1A)

Summary

Introduction

Lysophosphatidic acid (LPA: 1- or 2-acyl-sn-glycerol-3-phosphate) is a bioactive lipid that can induce a number of cellular responses, including cell proliferation, migration and cytoskeletal reorganization, most of which are mediated through six defined G-protein-coupled receptors (GPCRs) specific to LPA1,2. We previously designed and synthesized LPA analogs similar to 2-acyl-LPA (LPA with a fatty acid at the sn-2 position), so-called “T-series” compounds, in which a ring structure derived from carbohydrates is introduced as a scaffold instead of a glycerol backbone[11]. These analogs have restricted conformational flexibility due to the sugar ring structure and show unique activity for LPA1–3 in Ca2+ and migration assays. To clarify the molecular mechanism underlying the LPA-induced pressor response, we examined whether the LPA receptors cloned so far (LPA1–6) are involved in LPA-induced transient hypertension by utilizing a combination of LPA receptor KO mice and LPA analogs. We demonstrate that LPA6 signaling is crucial for normal vasoactivity and vascular development

Methods

Results

Conclusion