High salt diet modulates vascular response in A2AAR (+/+) and A 2AAR (-/-) mice: role of sEH, PPARγ, and K ATP channels.
This study aims to investigate the signaling mechanism involved in HS-induced modulation of adenosine-mediated vascular tone in the presence or absence of adenosine A2A receptor (A2AAR). We hypothesized that HS-induced enhanced vascular relaxation through A2AAR and epoxyeicosatrienoic acid (EETs) is dependent on peroxisome proliferator-activated receptor gamma (PPARγ) and ATP-sensitive potassium channels (KATP channels) in A2AAR(+/+) mice, while HS-induced vascular contraction to adenosine is dependent on soluble epoxide hydrolase (sEH) that degrades EETs in A2AAR(-/-) mice. Organ bath and Western blot techniques were conducted in HS (4 % NaCl) and normal salt (NS, 0.45 % NaCl)-fed A2AAR(+/+) and A2AAR(-/-) mouse aorta. We found that enhanced vasodilation to A2AAR agonist, CGS 21680, in HS-fed A2AAR(+/+) mice was blocked by PPARγ antagonist (T0070907) and KATP channel blocker (Glibenclamide). Also, sEH inhibitor (AUDA)-dependent vascular relaxation was mitigated by PPARγ antagonist. PPARγ agonist (Rosiglitazone)-induced relaxation in HS-A2AAR(+/+) mice was attenuated by KATP channel blocker. Conversely, HS-induced contraction in A2AAR(-/-) mice was attenuated by sEH inhibitor. Overall, findings from this study that implicates the contribution of EETs, PPARγ and KATP channels downstream of A2AAR to mediate enhanced vascular relaxation in response to HS diet while, role of sEH in mediating vascular contraction in HS-fed A2AAR(-/-) mice.
Department of Physiology & Pharmacology/Department of Basic Pharmaceutical Sciences, Center for Cardiovascular and Respiratory Sciences, School of Medicine/School of Pharmacy, West Virginia University, Biomedical Research Building, 2nd Floor, Room # 220, 3051 Health Science Center - North 1 Medical Center Drive, P. O. Box 9229, Morgantown, WV, 26506-9229, USA.
Isha
I
Pradhan
Catherine
C
Ledent
S Jamal
SJ
Mustafa
Christophe
C
Morisseau
Mohammed A
MA
Nayeem
D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000502:physiology*; D001095:Arachidonic Acids / Q000378:metabolism; D001549:Benzamides / Q000008:administration & dosage; D004791:Enzyme Inhibitors / Q000008:administration & dosage; D004851:Epoxide Hydrolases / Q000378:metabolism*; D054086:KATP Channels / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D047495:PPAR gamma / Q000235:genetics / Q000378:metabolism*; D011725:Pyridines / Q000008:administration & dosage; D043705:Receptor, Adenosine A2A / Q000235:genetics* / Q000378:metabolism; D012965:Sodium Chloride / Q000008:administration & dosage; D014664:Vasodilation / Q000187:drug effects
D001095:Arachidonic Acids; D001549:Benzamides; D004791:Enzyme Inhibitors; D054086:KATP Channels; D047495:PPAR gamma; D011725:Pyridines; D043705:Receptor, Adenosine A2A; C458508:T 0070907; D012965:Sodium Chloride; D004851:Epoxide Hydrolases