Adenosine A<sub>2A</sub> receptor modulates vascular response in soluble epoxide hydrolase-null mice through CYP-epoxygenases and PPARγ

Nayeem, Mohammed; Pradhan, Isha; Mustafa, S. Jamal; Morisseau, Christophe; Falck, John R.; Zeldin, Darryl C.

doi:10.1152/ajpregu.00213.2012

Cited by 21 publications

(113 citation statements)

References 63 publications

Supporting

Mentioning

103

Contrasting

Order By: Relevance

“…2a), indicating the involvement of PPARγ downstream of A 2A AR to produce enhanced vascular relaxation in mice in response to HS diet. This finding is in agreement with our previous published work [39] and others [27, 40] and confirms the contribution of PPARγ in A 2A AR-mediated vascular response.…”

Section: Discussionsupporting

confidence: 94%

“…6), implicating the contribution of K ATP channel in PPARγ-mediated vascular relaxation. Taken together, these data suggest that A 2A AR-EETs-PPARγ pathway produces vascular relaxation through K ATP channel which is consistent with our earlier reports [10, 39], suggesting that PPARγ elicits relaxation in both mouse vascular and human pulmonary arteries by activating K ATP channels [31]. …”

Section: Discussionsupporting

confidence: 92%

See 1 more Smart Citation

High salt diet modulates vascular response in A2AAR+/+ and A2AAR−/− mice: role of sEH, PPARγ, and KATP channels

et al. 2015

Self Cite

View full text Add to dashboard Cite

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.

show abstract

Section: Discussionsupporting

confidence: 94%

Section: Discussionsupporting

confidence: 92%

High salt diet modulates vascular response in A2AAR+/+ and A2AAR−/− mice: role of sEH, PPARγ, and KATP channels

et al. 2015

Self Cite

View full text Add to dashboard Cite

show abstract

“…Various studies revealed that a decrease in A 1 AR levels closely followed a decrease in sEH expression, and vice versa in sEH −/− and A 2A AR −/− mouse aortas [19, 21]. Additionally, sEH inhibition reduced A 1 AR-dependent aortic contractions in A 2A AR −/− mice [21].…”

Section: Discussionmentioning

confidence: 99%

“…We previously reported enhanced adenosine receptors (AR)-dependent vascular relaxation in the aorta of sEH knockout ( −/− ) mice [19]. This increase in relaxation was attributed to enhanced A 2A AR and decreased A 1 AR protein expression [19]. In A 2A AR −/− mouse aorta, we found higher expression of A 1 AR [20] and sEH [21].…”

Section: Introductionmentioning

confidence: 99%

“…Stimulation of A 1 AR or A 3 AR results in vascular contraction, while stimulation of A 2A AR or A 2B AR produces vascular relaxation [18]. We previously reported enhanced adenosine receptors (AR)-dependent vascular relaxation in the aorta of sEH knockout ( −/− ) mice [19]. This increase in relaxation was attributed to enhanced A 2A AR and decreased A 1 AR protein expression [19].…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Vascular endothelial over-expression of soluble epoxide hydrolase (Tie2-sEH) enhances adenosine A1 receptor-dependent contraction in mouse mesenteric arteries: role of ATP-sensitive K+ channels

et al. 2016

Self Cite

View full text Add to dashboard Cite

Soluble epoxide hydrolase (sEH) converts epoxyeicosatrienoic acids that are endothelium-derived hyperpolarizing factors into less active dihydroxyeicosatrienoic acids. Previously, we reported a decrease in adenosine A1 receptor (A1AR) protein levels in sEH knockout (sEH−/−) and an increase in sEH and A1AR protein levels in A2AAR−/− mice. Additionally, KATP channels are involved in adenosine receptor (AR)-dependent vascular relaxation. Thus, we hypothesize that a potential relationship may exist among sEH overexpression, A1AR up-regulation, inactivation of KATP channels and increased in vascular tone. We performed DMT myograph muscle tension measurements and western blot analysis in isolated mouse mesenteric arteries (MAs) from wild type (WT) and endothelial over-expression of sEH (Tie2-sEH Tr) mice. Our data revealed that NECA (a non-selective adenosine receptors agonist)-induced relaxation was significantly reduced in Tie2-sEH Tr mice, and CCPA (A1AR agonist)-induced contraction was increased in Tie2-sEH Tr mice. A1AR-dependent contraction in Tie2-sEH Tr mice was significantly attenuated by pharmacological inhibition of CYP4A (HET0016, 10 μM), PKCα (GO6976, 1 μM), and ERK1/2 (PD58059, 1 μM). Our western blot analysis revealed significantly higher basal protein expression of CYP4A, A1AR, and reduced p-ERK in MAs of Tie2-sEH Tr mice. Notably, pinacidil (KATP channel opener)-induced relaxation was also significantly reduced in MAs of Tie2-sEH Tr mice. Furthermore, KATP channel-dependent relaxation in MAs was enhanced by inhibition of PKCα and ERK1/2 in WT but not Tie2-sEH Tr mice. In conclusion, our data suggests that over-expression of sEH enhances A1AR-dependent contraction and reduces KATP channel-dependent relaxation in MAs. These results suggest a possible interaction between sEH, A1AR, and KATP channels in regulating vascular tone.

show abstract

Ephx2-gene deletion affects acetylcholine-induced relaxation in angiotensin-II infused mice: role of nitric oxide and CYP-epoxygenases

et al. 2019

Self Cite

View full text Add to dashboard Cite

Previously, we showed that adenosine A 2A receptor-induces relaxation independent of NO in soluble epoxide hydrolase-null mice (Am J Physiol Regul Integr Comp Physiol 304: R23-R32, 2013). Currently, we hypothesize that Ephx2-gene deletion affects acetylcholine (Ach)-induced relaxation which is independent of A 2A AR but dependent on NO and CYP-epoxygenases. Ephx2 −/− aortas showed a lack of sEH (97.1%, p<0.05) but an increase in microsomal epoxide hydrolase (mEH, 37%, p<0.05) proteins compared to C57Bl/6 mice, and no change in CYP2C29 and CYP2J protein (p>0.05). Ach-induced response was tested with nitro-L-arginine methyl ester (L-NAME) NO-inhibitor; 10 −4 M, N-(methylsulfonyl)-2-(2-propynyloxy)-benzenehexanamide (MS-PPOH) (CYP-epoxygenase inhibitor; 10 −5 M), 14,15-epoxyeicosa-5(Z)-enoic acid (14,15-EEZE, an epoxyeicosatrienoic acid-antagonist; 10 −5 M), SCH-58261 (A 2A AR-antagonist; 10 −6 M) and angiotensin-II (Ang-II, 10 −6 M). In Ephx2 −/− mice, Ach-induced relaxation was not different from C57Bl/6 mice except at 10 −5 M (92.75 ± 2.41 vs. 76.12 ± 3.34, P<0.05). However, Achinduced relaxation was blocked by L-NAME (Ephx2 −/− : 23.74 ± 3.76% and C57Bl/6: 11.61 ± 2.82%), MS-PPOH (Ephx2 −/− : 48.16 ± 6.53% and C57Bl/6: 52.27 ± 7.47%) and 14,15-EEZE (Ephx2 −/− : 44.29 ± 8.33% and C57Bl/6: 39.27 ± 7.47%) vs. non-treated (P<0.05). But, it did not block by SCH-58261 (Ephx2 −/− : 68.75 ± 11.41% and C57Bl/6: 66.26 ± 9.43%, P >0.05) vs. nontreated (P>0.05). Interestingly, Ang-II attenuates less relaxation in Ehx2 −/− vs. C57Bl/6 mice (58.80 ± 7.81% vs. 45.92 ± 7.76, P <0.05). Our data suggests that Ach-induced relaxation in

show abstract

Adenosine A_2A receptor modulates vascular response in soluble epoxide hydrolase-null mice through CYP-epoxygenases and PPARγ

Abstract: Nayeem MA, Pradhan I, Mustafa SJ, Morisseau C, Falck JR, Zeldin DC. Adenosine A2A receptor modulates vascular response in soluble epoxide hydrolase-null mice through CYP-epoxygenases and PPAR␥.

Cited by 21 publications

References 63 publications

High salt diet modulates vascular response in A2AAR+/+ and A2AAR−/− mice: role of sEH, PPARγ, and KATP channels

High salt diet modulates vascular response in A2AAR+/+ and A2AAR−/− mice: role of sEH, PPARγ, and KATP channels

Vascular endothelial over-expression of soluble epoxide hydrolase (Tie2-sEH) enhances adenosine A1 receptor-dependent contraction in mouse mesenteric arteries: role of ATP-sensitive K+ channels

Ephx2-gene deletion affects acetylcholine-induced relaxation in angiotensin-II infused mice: role of nitric oxide and CYP-epoxygenases

Contact Info

Product

Resources

About

Adenosine A2A receptor modulates vascular response in soluble epoxide hydrolase-null mice through CYP-epoxygenases and PPARγ

Abstract: Nayeem MA, Pradhan I, Mustafa SJ, Morisseau C, Falck JR, Zeldin DC. Adenosine A2A receptor modulates vascular response in soluble epoxide hydrolase-null mice through CYP-epoxygenases and PPAR␥.

Cited by 21 publications

References 63 publications

High salt diet modulates vascular response in A2AAR+/+ and A2AAR−/− mice: role of sEH, PPARγ, and KATP channels

High salt diet modulates vascular response in A2AAR+/+ and A2AAR−/− mice: role of sEH, PPARγ, and KATP channels

Vascular endothelial over-expression of soluble epoxide hydrolase (Tie2-sEH) enhances adenosine A1 receptor-dependent contraction in mouse mesenteric arteries: role of ATP-sensitive K+ channels

Ephx2-gene deletion affects acetylcholine-induced relaxation in angiotensin-II infused mice: role of nitric oxide and CYP-epoxygenases

Contact Info

Product

Resources

About

Adenosine A_2A receptor modulates vascular response in soluble epoxide hydrolase-null mice through CYP-epoxygenases and PPARγ