Doxycycline attenuates isoproterenol- and transverse aortic banding-induced cardiac hypertrophy in mice
Doxycycline attenuates isoproterenol- and transverse aortic banding-induced cardiac hypertrophy in mice
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DOI：
10.1124/jpet.107.133975
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发表时间：
2008-03-01
影响因子：
3.5
通讯作者：
Garner, Harold R.
中科院分区：
文献类型：
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作者：
Errami, Mounir;Galindo, Cristi L.;Garner, Harold R.
美国食品和药物管理局批准的抗生素多西环素（DOX）抑制基质金属蛋白酶，这有助于心脏肥大（CH）的发展。我们假设，DOX可能作为CH的治疗。DOX的疗效进行了测试，在两个小鼠模型的CH：诱导的β-肾上腺素能激动剂异丙肾上腺素（ISO）和诱导的横向主动脉带。DOX在这些模型中显著减弱CH，导致肥大表型的显著降低和较低的心脏/体重比（p < 0.05，n >= 6）。正如预期的那样，ISO增加基质金属蛋白酶（MMP）2和9的活动，并给予DOX逆转这种影响。使用微阵列检查正常、ISO-和ISO + DOX处理的小鼠的转录谱，并通过实时逆转录酶-聚合酶链反应证实结果。基因（206）在正常和ISO小鼠之间差异表达，在ISO-和ISO + DOX-处理的小鼠之间可逆地改变，表明它们在CH发展和DOX-诱导的改善中的潜在作用。这些基因包括参与调节细胞增殖和命运、应激和免疫反应、细胞骨架和细胞外基质组织以及心脏特异性信号转导的基因。整体基因表达谱表明MMP 2/9失活不是DOX发挥其有益作用的唯一机制。蛋白质印迹分析确定了与CH相关的潜在信号传导事件，包括内皮分化鞘脂G蛋白偶联受体1受体的上调和细胞外信号调节激酶p38的激活，以及转录因子激活转录因子-2，这些在给予DOX后减少。这些结果表明，DOX可能被评估为一种潜在的CH治疗剂，也提供了潜在的信号传导机制，以研究CH表型的发展和消退。
The United States Food and Drug Administration-approved antibiotic doxycycline (DOX) inhibits matrix metalloproteases, which contribute to the development of cardiac hypertrophy (CH). We hypothesized that DOX might serve as a treatment for CH. The efficacy of DOX was tested in two mouse models of CH: induced by the beta-adrenergic agonist isoproterenol (ISO) and induced by transverse aortic banding. DOX significantly attenuated CH in these models, causing a profound reduction of the hypertrophic phenotype and a lower heart/body weight ratio (p < 0.05, n >= 6). As expected, ISO increased matrix metalloprotease (MMP) 2 and 9 activities, and administration of DOX reversed this effect. Transcriptional profiles of normal, ISO-, and ISO + DOX-treated mice were examined using microarrays, and the results were confirmed by real-time reverse transcriptase-polymerase chain reaction. Genes (206) were differentially expressed between normal and ISO mice that were reversibly altered between ISO- and ISO + DOX-treated mice, indicating their potential role in CH development and DOX-induced improvement. These genes included those involved in the regulation of cell proliferation and fate, stress, and immune responses, cytoskeleton and extracellular matrix organization, and cardiac-specific signal transduction. The overall gene expression profile suggested that MMP2/9 inactivation was not the only mechanism whereby DOX exerts its beneficial effects. Western blot analysis identified potential signaling events associated with CH, including up-regulation of endothelial differentiation sphingolipid G-protein-coupled receptor 1 receptor and activation of extracellular signal-regulated kinase, p38, and the transcription factor activating transcription factor-2, which were reduced after administration of DOX. These results suggest that DOX might be evaluated as a potential CH therapeutic and also provide potential signaling mechanisms to investigate in the context of CH phenotype development and regression.