Journal article
Lysophosphatidic acid acts on LPA 1 receptor to increase H 2 O 2 during flow-induced dilation in human adipose arterioles: LPA regulates the mediator of FID through LPA 1 receptor
British journal of pharmacology, Vol.175(22), pp.4266-4280
11/2018
DOI: 10.1111/bph.14492
PMCID: PMC6193883
PMID: 30153326
Abstract
Background and Purpose: NO produces arteriolar flow-induced dilation (FID) in healthy subjects but is replaced by mitochondria-derived hydrogen peroxide (mtH2O2) in patients with coronary artery disease (CAD). Lysophosphatidic acid (LPA) is elevated in patients with risk factors for CAD, but its functional effect in arterioles is unknown. We tested whether elevated LPA changes the mediator of FID from NO to mtH2O2 in human visceral and subcutaneous adipose arterioles. Experimental Approach: Arterioles were cannulated on glass micropipettes and pressurized to 60 mmHg. We recorded lumen diameter after graded increases in flow in the presence of either NOS inhibition (L-NAME) or H2O2 scavenging (Peg-Cat) ± LPA (10 μM, 30 min), ±LPA1/LPA3 receptor antagonist (Ki16425) or LPA2 receptor antagonist (H2L5186303). We analysed LPA receptor RNA and protein levels in human arterioles and human cultured endothelial cells. Key Results: FID was inhibited by L-NAME but not Peg-Cat in untreated vessels. In vessels treated with LPA, FID was of similar magnitude but inhibited by Peg-Cat while L-NAME had no effect. Rotenone attenuated FID in vessels treated with LPA indicating mitochondria as a source of ROS. RNA transcripts from LPA1 and LPA2 but not LPA3 receptors were detected in arterioles. LPA1 but not LPA3 receptor protein was detected by Western blot. Pretreatment of vessels with an LPA1/LPA3, but not LPA2, receptor antagonist prior to LPA preserved NO-mediated dilation. Conclusions and Implications: These findings suggest an LPA1 receptor-dependent pathway by which LPA increases arteriolar release of mtH2O2 as a mediator of FMD.
Details
- Title: Subtitle
- Lysophosphatidic acid acts on LPA 1 receptor to increase H 2 O 2 during flow-induced dilation in human adipose arterioles: LPA regulates the mediator of FID through LPA 1 receptor
- Creators
- Dawid S Chabowski - Medical College of WisconsinAndrew O Kadlec - Medical College of WisconsinKarima Ait-Aissa - Medical College of WisconsinJoseph C Hockenberry - Medical College of WisconsinPaul J Pearson - Medical College of WisconsinAndreas M Beyer - Medical College of WisconsinDavid D Gutterman - Medical College of Wisconsin
- Resource Type
- Journal article
- Publication Details
- British journal of pharmacology, Vol.175(22), pp.4266-4280
- DOI
- 10.1111/bph.14492
- PMID
- 30153326
- PMCID
- PMC6193883
- ISSN
- 0007-1188
- eISSN
- 1476-5381
- Grant note
- DOI: 10.13039/100000968, name: American Heart Association, award: 16POST26430075, 17PRE33410986; DOI: 10.13039/100000002, name: National Institutes of Health, award: 1R01 HL133029, R01 HL113612, R01 HL135901
- Language
- English
- Date published
- 11/2018
- Academic Unit
- Cardiovascular Medicine; Internal Medicine
- Record Identifier
- 9984359858202771
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