Sepiapterin enhances angiogenesis and functional recovery in mice after myocardial infarction
Sepiapterin enhances angiogenesis and functional recovery in mice after myocardial infarction
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DOI：
10.1152/ajpheart.00525.2011
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发表时间：
2011-11-01
影响因子：
4.8
通讯作者：
Iwasaka, Toshiji
中科院分区：
文献类型：
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作者：
Shimazu, Takayuki;Otani, Hajime;Iwasaka, Toshiji
[10]张文，张文. Sepiapterin增强心肌梗死后小鼠血管生成和功能恢复。Am J Physiol Heart Circ Physiol 301：H2061-H2072，2011.首次发表于2011年9月2日; doi：10.1152/ajpheart.00525.2011。一氧化氮合酶（NOS）的解偶联与心肌梗死（MI）后左心室（LV）重构和功能障碍有关。我们假设诱导型一氧化氮合酶（iNOS）在心肌梗死后左室重塑中起着至关重要的作用，这取决于其偶联状态。在野生型、iNOS敲除（iNOS（-/-））、内皮NOS敲除（eNOS（-/-））和神经元NOS敲除（nNOS（-/-））小鼠中产生MI。心肌梗死后iNOS和nNOS表达增加，与硝基酪氨酸形成增加相关。心肌梗死后4 wk，eNOS（-/-）小鼠心肌纤维化面积、左室舒张末期容积和射血分数较其他基因型小鼠恶化。心肌梗死后，心肌组织中GTP环化水解酶的表达减少，四氢生物蝶呤（BH 4）减少。心肌梗死后口服sepiapterin增加了二氢生物蝶呤（BH 2），BH 4和BH 4-BH 2比，但不是假手术心脏。BH 4-BH 2比例的增加与硝基酪氨酸形成的抑制和亚硝酸盐加硝酸盐的增加有关。然而，在iNOS（-/-）小鼠中，这种NOS解偶联的抑制被钝化。在野生型、eNOS（-/-）和nNOS（-/-）小鼠中，Sepiapterin增加毛细血管密度，并防止MI后LV重塑和功能障碍，但不影响iNOS（-/-）小鼠。N-ω-硝基-L-精氨酸甲酯消除了sepiapterin诱导的亚硝酸盐+硝酸盐和血管生成的增加，并阻断了sepiapterin对LV重塑和功能的有益作用。这些结果表明，sepiapterin通过激活BH 4合成的补救途径和增加主要来源于iNOS的生物可利用的一氧化氮，增强MI后的血管生成和功能恢复。
Shimazu T, Otani H, Yoshioka K, Fujita M, Okazaki T, Iwasaka T. Sepiapterin enhances angiogenesis and functional recovery in mice after myocardial infarction. Am J Physiol Heart Circ Physiol 301: H2061-H2072, 2011. First published September 2, 2011; doi:10.1152/ajpheart.00525.2011.-Uncoupling of nitric oxide synthase (NOS) has been implicated in left ventricular (LV) remodeling and dysfunction after myocardial infarction (MI). We hypothesized that inducible NOS (iNOS) plays a crucial role in LV remodeling after MI, depending on its coupling status. MI was created in wild-type, iNOS-knockout (iNOS(-/-)), endothelial NOS-knockout (eNOS(-/-)), and neuronal NOS-knockout (nNOS(-/-)) mice. iNOS and nNOS expressions were increased after MI associated with an increase in nitrotyrosine formation. The area of myocardial fibrosis and LV end-diastolic volume and ejection fraction were more deteriorated in eNOS(-/-) mice compared with other genotypes of mice 4 wk after MI. The expression of GTP cyclohydrolase was reduced, and tetrahydrobiopterin (BH4) was depleted in the heart after MI. Oral administration of sepiapterin after MI increased dihydrobiopterin (BH2), BH4, and BH4-to-BH2 ratio in the infarcted but not sham-operated heart. The increase in BH4-to-BH2 ratio was associated with inhibition of nitrotyrosine formation and an increase in nitrite plus nitrate. However, this inhibition of NOS uncoupling was blunted in iNOS(-/-) mice. Sepiapterin increased capillary density and prevented LV remodeling and dysfunction after MI in wild-type, eNOS(-/-), and nNOS(-/-) but not iNOS(-/-) mice. N-omega-nitro-L-arginine methyl ester abrogated sepiapterin-induced increase in nitrite plus nitrate and angiogenesis and blocked the beneficial effects of sepiapterin on LV remodeling and function. These results suggest that sepiapterin enhances angiogenesis and functional recovery after MI by activating the salvage pathway for BH4 synthesis and increasing bioavailable nitric oxide predominantly derived from iNOS.