Effect of PAR2 in regulating TNF-α and NAD(P)H oxidase in coronary arterioles in type 2 diabetic mice.
Effect of PAR2 in regulating TNF-α and NAD(P)H oxidase in coronary arterioles in type 2 diabetic mice.
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DOI：
10.1007/s00395-010-0129-9
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发表时间：
2011-01
影响因子：
9.5
通讯作者：
Zhang C
中科院分区：
文献类型：
--
作者：
Park Y;Yang J;Zhang H;Chen X;Zhang C
蛋白酶活化受体-2 （PAR2）在内皮细胞中表达并介导内皮依赖性血管舒张。我们假设PAR2调节肿瘤坏死因子-α (TNF-α)诱导的2型糖尿病（db/db）小鼠冠状动脉功能障碍。为了验证这一点，将WT对照组、db/db、经PAR2拮抗剂FSLLRY-NH2 （db/db+ FSLLRY-NH2）处理的db/db小鼠和TNF （dbTNF - /dbTNF -）无效的db/db小鼠的冠状动脉分离并加压（60 cmH2O），无血流。尽管在WT、db/db、db/db+ fslly - nh2和dbTNF - /dbTNF -中，内皮依赖性乙酰胆碱(ACh)-和血流介导的血管舒张作用在db/db小鼠中受损，但在dbTNF - /dbTNF -小鼠和PAR2拮抗剂处理的db/db小鼠中增强。NOS抑制剂ng -硝基-l-精氨酸甲酯（l-NAME）可显著降低乙酰胆碱诱导的WT、dbTNF - /dbTNF -和db/db+ FSLLRY-NH2的舒张，但不改变db/db小鼠的血管舒张。相比之下，环氧化酶（COX）抑制剂吲哚美辛（indomethacin, Indo）在这四组小鼠中没有改变疼痛诱导的血管舒张。PAR2激活肽（PAR2- ap, 2-Furoyl-LIGRLO-am）诱导的扩张性在db/db小鼠中高于WT、dbTNF - /dbTNF -和db/db小鼠。这些影响通过剥蚀或l-NAME或Indo的存在而消除。与WT小鼠相比，db/db小鼠心脏和离体冠状动脉中TNF-α、PAR2、gp91phox和p47phox的蛋白表达更高。给db/db小鼠PAR2拮抗剂可降低TNF-α、gp91phox和PAR2的蛋白表达。与db/db小鼠相比，dbTNF - /dbTNF -中gp91phox和p47phox的蛋白表达较低。这些结果表明，PAR2通过上调TNF-α的表达/产生和激活NAD(P)H氧化酶亚基p47phox，在2型糖尿病内皮功能障碍中起关键作用。
Protease-activated receptor-2 (PAR2) is expressed in endothelial cells and mediates endothelium-dependent vasodilation. We hypothesized that PAR2 regulates tumor necrosis factor-alpha (TNF-α)-induced coronary arteriolar dysfunction in type 2 diabetic (db/db) mice. To test this, coronary arterioles from WT control, db/db, db/db mice treated with PAR2 antagonist FSLLRY–NH2 (db/db+FSLLRY–NH2) and db/db mice null for TNF (dbTNF–/dbTNF–) were isolated and pressurized (60 cmH2O) without flow. Although vasodilation to the endothelium-independent vasodilator sodium nitroprusside (SNP) was not different among WT, db/db, db/db+FSLLRY–NH2 and dbTNF–/dbTNF–, endothelium-dependent acetylcholine (ACh)- and flow-mediated vasodilation were impaired in db/db mice but were enhanced in dbTNF–/dbTNF– mice and db/db mice treated with PAR2 antagonist. NOS inhibitor NG-nitro-l-arginine-methyl ester (l-NAME) significantly reduced ACh-induced dilation in WT, dbTNF–/dbTNF– and db/db+FSLLRY–NH2, but did not alter the vasodilation in db/db mice. In contrast, cyclooxygenase (COX) inhibitor indomethacin (Indo) did not alter ACh-induced vasodilation in these four groups of mice. PAR2-activating peptide (PAR2-AP, 2-Furoyl-LIGRLO-am)-induced dilation was higher in db/db mice than that in WT, dbTNF–/dbTNF– and db/db mice treated with PAR2 antagonist. These effects were abolished by denudation, or in the presence of l-NAME or Indo. Protein expressions of TNF-α, PAR2, gp91phox and p47phox in the heart and isolated coronary arterioles were higher in db/db mice compared to WT mice. Administration of PAR2 antagonist to db/db mice reduced protein expression of TNF-α, gp91phox and PAR2. Protein expression of gp91phox and p47phox was lower in dbTNF–/dbTNF– compared to db/db mice. These results indicate that PAR2 plays a pivotal role in endothelial dysfunction in type 2 diabetes by up-regulating the expression/production of TNF-α and activating NAD(P)H oxidase subunit p47phox.
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影响因子：
7.7
作者：
Duncan, BB;Schmidt, MI;Heiss, G
通讯作者：
Heiss, G
影响因子：
4.8
作者：
Nystedt, S;Ramakrishnan, V;Sundelin, J
通讯作者：
Sundelin, J
影响因子：
9.5
作者：
Ihm, Sang-Hyun;Chang, Kiyuk;Kim, Jae-Hyung
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影响因子：
6
作者：
Ebrahimian, Teni G.;Heymes, Christophe;Silvestre, Jean-Sebastien
通讯作者：
Silvestre, Jean-Sebastien
DOI：
10.1152/ajplung.00286.2003
发表时间：
2004-02-01
影响因子：
4.9
作者：
Lan, RS;Stewart, GA;Henry, PJ
通讯作者：
Henry, PJ