High-salt diet enhances mouse aortic relaxation through adenosine A2A receptor via CYP epoxygenases
High-salt diet enhances mouse aortic relaxation through adenosine A2A receptor via CYP epoxygenases
复制标题
DOI：
10.1152/ajpregu.90798.2008
复制
发表时间：
2009-03-01
影响因子：
2.8
通讯作者：
Mustafa, S. Jamal
中科院分区：
文献类型：
--
作者：
Nayeem, Mohammed A.;Ponnoth, Dovenia S.;Mustafa, S. Jamal
Nayeem MA，Ponnoth DS，Boegehold MA，Zeldin DC，法尔克JR，Mustafa SJ.高盐饮食通过腺苷A（2A）受体和腺苷酸环氧合酶增强小鼠主动脉舒张。Am J Physiol Regul Integr Comp Physiol 296：R567-R574，2009。首次发表于2008年12月24日; doi：10.1152/ajpregu.90798.2008。我们假设A（2A）腺苷受体（A（2A）AR）通过细胞色素P450（CYP）-环氧合酶促进小鼠主动脉舒张，并有助于避免盐敏感性。使用来自维持高盐（HS; 7%NaCl）或正常盐（NS; 0.45%NaCl）饮食4-5周的雄性小鼠的主动脉。5 '-N-乙基甲酰胺腺苷的浓度-响应曲线（10（-11）-10（-5）M）（NECA;非选择性腺苷类似物）和CGS 21680（A2 A AR激动剂）与包括ZM 241385在内的不同拮抗剂一起获得（A2 A AR拮抗剂; 10（-6）M），SCH 58261（A（2A）AR拮抗剂; 10（-6）M），N-ω-硝基-L-精氨酸甲酯（L-NAME;内皮一氧化氮合酶抑制剂; 10（-4）M）和抑制剂，包括甲磺酰基-炔丙氧基苯基己酰胺（MS-PPOH; CYP 4A抑制剂; 10（-5）M）、14，15-环氧二十碳-5（z）-烯酸（14，15-EEZE; EET拮抗剂; 10（-5）M）、二溴-十二碳烯基-甲基磺酰亚胺（DDMS; CYP 4A抑制剂; 10（-5）M）和HET 0016（20-HETE抑制剂; 10（-5）M）。在10（-7）M的NECA时，HS的舒张（+ 22.58 ± 3.12%）与NS的收缩（- 10.62 ± 6.27%，P < 0.05）相比有显著性差异。ZM 241385可改变HS对NECA的收缩反应（P < 0.05）。在10（-7）M的CGS 21680下，HS（+ 32.04 +/-3.08%）与NS（+ 10.45 +/-1.34%，P < 0.05）相比观察到显著的舒张作用。SCH 58261、L-NAME、MS-PPOH和14，15-EEZE使CGS 21680引起的HS舒张变为收缩（P < 0.05）。有趣的是，在NS中，DDMS和HET 0016改变了CGS 21680对松弛的反应（P < 0.05）;然而，在DDMS、HET 0016处理的HS和NS与未处理的HS组之间没有发现显著差异（P > 0.05）。与NS组相比，HS组小鼠主动脉和肾脏中CYP 2C 29蛋白表达分别上调55%和74%（P < 0.05）。NS组主动脉和肾脏中CYP 4A蛋白表达分别比HS组高30.30%和35.70%（P < 0.05）。与NS相比，HS中A（1）AR下调，而A（2A）AR上调。这些数据表明，HS可能通过A2 A AR激活CYP 2C 29，引起舒张，而NS可能有助于上调CYP 4A，引起收缩。
Nayeem MA, Ponnoth DS, Boegehold MA, Zeldin DC, Falck JR, Mustafa SJ. High-salt diet enhances mouse aortic relaxation through adenosine A(2A) receptor via CYP epoxygenases. Am J Physiol Regul Integr Comp Physiol 296: R567-R574, 2009. First published December 24, 2008; doi: 10.1152/ajpregu.90798.2008. -We hypothesize that A(2A) adenosine receptors (A(2A) AR) promote aortic relaxation in mice through cytochrome P450 ( CYP)-epoxygenases and help to avoid salt sensitivity. Aortas from male mice maintained on a high-salt (HS; 7% NaCl) or normal-salt (NS; 0.45% NaCl) diet for 4-5 wks were used. Concentration-response curves (10(-11)-10(-5) M) for 5'-N-ethylcarboxamidoadenosine ( NECA; a nonselective adenosine analog) and CGS 21680 ( A2A AR agonist) were obtained with different antagonists including ZM 241385 ( A2A AR antagonist; 10(-6) M), SCH 58261 (A(2A) AR antagonist; 10(-6) M), N-omega-nitro-L-arginine methyl ester (L-NAME; endothelial nitric oxide synthase inhibitor; 10(-4) M) and inhibitors including methylsulfonyl-propargyloxyphenylhexanamide (MS-PPOH; CYP epoxygenases inhibitor; 10(-5)M), 14,15-epoxyeicosa-5(z)-enoic acid ( 14,15-EEZE; EET antagonist; 10(-5)M), dibromo-dodecenyl-methylsulfimide ( DDMS; CYP4A inhibitor; 10(-5)M), and HET0016 (20-HETE inhibitor; 10(-5)M). At 10(-7) M of NECA, significant relaxation in HS (+ 22.58 +/- 3.12%) was observed compared with contraction in NS ( - 10.62 +/- 6.27%, P < 0.05). ZM 241385 changed the NECA response to contraction ( P < 0.05) in HS. At 10(-7) M of CGS 21680, significant relaxation in HS ( + 32.04 +/- 3.08%) was observed compared with NS ( + 10.45 +/- 1.34%, P < 0.05). SCH 58261, L-NAME, MS-PPOH, and 14,15-EEZE changed the CGS 21680-induced relaxation to contraction ( P < 0.05) in HS. Interestingly, DDMS and HET0016 changed CGS 21680 response to relaxation ( P < 0.05) in NS; however, there was no significant difference found between DDMS, HET0016-treated HS and NS vs. nontreated HS group ( P > 0.05). CYP2C29 protein was 55% and 74% upregulated in HS vs. NS ( P < 0.05) mice aorta and kidney, respectively. CYP4A protein was 30.30% and 35.70% upregulated in NS vs. HS ( P < 0.05) mice aorta and kidneys, respectively. A(1) AR was downregulated, whereas A(2A) AR was upregulated in HS compared with NS. These data suggest that HS may activate CYP2C29 via A2A AR, causing relaxation, whereas NS may contribute to the upregulation of CYP4A causing contraction.