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Role of PPAR‐γ in A2AAR‐mediated vascular relaxation in high salt‐fed mice (849.4)
Author(s) -
Pradhan Isha,
Zeldin Darryl,
Ledent Catherine,
Falck John,
Mustafa Jamal,
Nayeem Mohammed
Publication year - 2014
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.28.1_supplement.849.4
Subject(s) - agonist , adenosine , medicine , adenosine receptor , endocrinology , receptor
High salt (HS)‐induced enhanced vascular response to adenosine is known to be mediated through adenosine A2A receptor (A2AAR) and cyp‐epoxygenase‐derived EETs (epoxyeicosatrienoic acid). The aim of this study is to investigate the mechanism involved in A2AAR‐mediated vascular reactivity in HS‐fed mice using A2AAR‐/‐ and A2AAR+/+ mice. We hypothesized that HS‐induced enhanced A2AAR‐EETs‐mediated vascular relaxation is dependent on PPAR‐ɣ (Peroxisome proliferator‐activated receptor gamma) in A2AAR+/+ mice and vascular contraction is dependent on less EETs in A2AAR‐/‐ mice. Organ bath and western blot studies were conducted with 4% (HS) and 0.18% NaCl (NS) diet fed A2AAR‐/‐ and A2AAR+/+ mice. A2AAR agonist, CGS‐21680, enhanced relaxation in HS‐A2AAR+/+ (+27.59 ± 4.7 vs. NS‐A2AAR+/+ +9.6 ± 7.6%), which was blocked by EET antagonist 14,15‐EEZE (1µM; ‐1.08 ± 2.95%) and PPAR‐ɣ antagonist T0070907 (0.1µM; 10.6 ± 1.84%, p<0.05). HS‐A2AAR+/+ had increased expression of cyp2j5 and PPAR‐ɣ compared to NS‐A2AAR+/+. Interestingly, PPAR‐ɣ was downregulated in HS‐A2AAR‐/‐ compared to HS‐A2AAR+/+ mice. Adenosine analog NECA (1µM) produced relaxation (+12.09 ±4.4 %, p<0.05) in HS‐A2AAR+/+ vs. contraction in HS‐A2AAR‐/‐ (‐57.29 ± 2.84%). NECA‐induced contraction in HS‐A2AAR‐/‐ was not affected by T0070907, but attenuated by the inhibitor of soluble epoxide hydrolase (sEH), the enzyme that metabolizes EETs (AUDA; 10 µM; NS: ‐15.23 ± 3.41 and HS: ‐6.62 ± 1.24%, p<0.05). Our data suggest that in A2AAR+/+ mice, HS enhances relaxation through A2AAR‐EETs via PPAR‐ɣ whereas, in A2AAR‐/‐ mice, HS promotes contraction through less availability of EETs and PPAR‐ɣ. Grant Funding Source : Supported by HL114559 to MAN, HL027339, HL094447 to SJM, GM31278 to JRF and z01‐ES025034 to DCZ