Date of Graduation
2014
Document Type
Dissertation
Degree Type
PhD
College
School of Pharmacy
Department
Pharmaceutical Sciences
Committee Chair
Mohammed A Nayeem
Committee Co-Chair
Gregory Dick
Committee Member
Pingnian He
Committee Member
Jason Huber
Committee Member
Jamal S Mustafa
Abstract
Alteration in vascular reactivity serves as a marker for cardiovascular disease. Enhancement of vasodilatory response through adenosine A2A receptor (A2AAR) signaling against high salt (HS) diet is speculated to be an adaptive response as salt-sensitive rats showed upregulation of A 2AAR and cyp-epoxygenases but salt-resistant rats did not. However, no direct evidence is available showing the compensatory role of A2A AR signaling upon salt loading. For this, understanding the functional and biochemical outcome of HS diet on vascular tone regulation and its underlying signaling mechanism in the presence and absence of A 2AAR is required. This dissertation was carried out to investigate the role of A2AAR and epoxyeicosatrienoic acid (EETs) on HS-modulated vascular reactivity and its signaling pathway involved using A2AAR +/+ and A2AAR-/- mice. Isometric tension measurement and western blot studies were conducted to evaluate aortic reactivity and underlying signaling mechanism in HS and normal salt (NS) fed A2A AR+/+ and A2AAR-/- mice. Our data demonstrated clear differences in vascular reactivity and their signaling mechanism between A2AAR+/+ and A2AAR -/- mice on a HS diet. HS diet enhanced vascular relaxation to adenosine in A2AAR+/+ mice, while HS diet amplified contraction to adenosine in A2AAR-/- mice. In the presence of A2AAR, we found that enhanced vascular relaxation to HS is mediated through A2AAR coupled with EETs that activate peroxisome proliferator activated receptor-gamma (PPARgamma) leading to opening of ATP-sensitive K+ (KATP) channels downstream. In contrary, in the absence of A 2AAR, HS-elicited amplified contraction is found to occur through loss of vasodilatory response and its signaling involving EETs and PPARgamma and increased vasoconstrictors such as adenosine A1 receptor (A1AR) and soluble epoxide hydrolase (sEH), an enzyme that degrades EETs. Most importantly, our finding revealed that increasing EETs availability through sEH inhibition could be a potential strategy to improve exaggerated vascular contraction in HS-fed A2AAR-/- mice.
Recommended Citation
Pradhan, Isha, "High salt diet-induced alteration in vascular reactivity in wild-type and adenosine A2A receptor null mice" (2014). Graduate Theses, Dissertations, and Problem Reports. 6446.
https://researchrepository.wvu.edu/etd/6446