Molecular mechanism of lysophosphatidic acid-induced hypertensive response

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

Research output: Contribution to journalArticlepeer-review

12 Citations (Scopus)

Abstract

Lysophosphatidic acid (LPA) is a blood-derived bioactive lipid with numerous biological activities exerted mainly through six defined G protein-coupled receptors (LPA 1 -LPA 6 ). 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 Gα 12/13 signaling. Consistent with this, the response was weakened in KO mice of LPA 4 , a Gα 12/13 -coupling LPA receptor. KO mice of another Gα 12/13 -coupling LPA receptor, LPA 6 , also showed an attenuated LPA-induced hypertensive response. However, LPA 6 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 LPA 4 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 LPA 4 .

Original languageEnglish
Article number2662
JournalScientific reports
Volume9
Issue number1
DOIs
Publication statusPublished - 2019 Dec 1

ASJC Scopus subject areas

  • General

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