TY - JOUR
T1 - Molecular mechanism of lysophosphatidic acid-induced hypertensive response
AU - Kano, Kuniyuki
AU - Matsumoto, Hirotaka
AU - Inoue, Asuka
AU - Yukiura, Hiroshi
AU - Kanai, Motomu
AU - Chun, Jerold
AU - Ishii, Satoshi
AU - Shimizu, Takao
AU - Aoki, Junken
N1 - Funding Information:
We thank ONO Pharmaceutical Co., Ltd for the gift of the ATX inhibitor. This work was supported by Grant-in-Aid for Scientific Research on Innovative Areas JP15H05899 (J.A.), KAKENHI grant JP17K08264 (A.I.); the PRIME JP17gm5910013 (A.I.) and the LEAP JP17gm0010004 (K.K., A.I. and J.A.) from the Japan Agency for Medical Research and Development (AMED). J.C. was supported by NIH R01 NS084398.
Publisher Copyright:
© 2019, The Author(s).
PY - 2019/12/1
Y1 - 2019/12/1
N2 - 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 .
AB - 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 .
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U2 - 10.1038/s41598-019-39041-4
DO - 10.1038/s41598-019-39041-4
M3 - Article
C2 - 30804442
AN - SCOPUS:85062070926
SN - 2045-2322
VL - 9
JO - Scientific Reports
JF - Scientific Reports
IS - 1
M1 - 2662
ER -