Inducible Nitric Oxide Synthase in Heart Tissue and Nitric Oxide in Serum of Trypanosoma cruzi-Infected Rhesus Monkeys: Association with Heart Injury
Inducible Nitric Oxide Synthase in Heart Tissue and Nitric Oxide in Serum of Trypanosoma cruzi-Infected Rhesus Monkeys: Association with Heart Injury
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DOI：
10.1371/journal.pntd.0001644
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发表时间：
2012-05-01
影响因子：
3.8
通讯作者：
Lannes-Vieira, Joseli
中科院分区：
文献类型：
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作者：
Espinola Carvalho, Cristiano Marcelo;Silverio, Jaline Coutinho;Lannes-Vieira, Joseli
背景：导致慢性恰加斯心脏病的因素仍然未知。高一氧化氮（NO）水平已被证明与患者心肌病的严重程度有关。此外，通过诱导型一氧化氮合酶（iNOS/NOS 2）产生的NO被认为在克氏锥虫控制中发挥作用。而T. cruzi控制和心脏损伤受到质疑。在此，我们使用慢性感染的恒河猴和iNOS/NOS 2缺陷（Nos 2（-/-））小鼠，探讨了iNOS/NOS 2衍生的NO在T.方法：用哥伦比亚克氏锥虫感染恒河猴、C57 BL/6和Nos 2（-/-）小鼠，克氏菌株用聚合酶链反应检测寄生虫DNA，T。采用免疫组化法检测心脏组织中Cruzi抗原和iNOS/NOS 2（+）细胞，Griess试剂法检测血清NO水平。通过心电图（ECG）、超声心动图（ECHO）、血清肌酸激酶同工酶（CK-MB）活性及心肌组织连接蛋白43（Cx43）表达等指标评价慢性感染猴心肌损伤程度。重要的是，慢性心肌炎与寄生虫持续存在有关。此外，Cx43丢失和CK-MB活性水平升高主要与心肌组织中浸润的iNOS/NOS 2（+）细胞和血清中NO水平相关。在Nos 2（-/-）小鼠中的研究进一步证实了iNOS/NOS 2-NO通路在T. Cruzi引起心肌细胞损伤和传导异常，与心脏组织中Cx43丢失有关。克氏病感染的恒河猴复制CCC的特征。此外，我们的数据支持T. Cruzi感染引起的心肌组织iNOS/NOS 2的持续存在和NO的过度产生可能是CCC严重程度的原因之一，主要是影响了心肌细胞电同步性的分子通路。这些发现为查加斯心脏病的治疗工具开辟了新的途径。
Background: The factors contributing to chronic Chagas' heart disease remain unknown. High nitric oxide (NO) levels have been shown to be associated with cardiomyopathy severity in patients. Further, NO produced via inducible nitric oxide synthase (iNOS/NOS2) is proposed to play a role in Trypanosoma cruzi control. However, the participation of iNOS/NOS2 and NO in T. cruzi control and heart injury has been questioned. Here, using chronically infected rhesus monkeys and iNOS/NOS2-deficient (Nos2(-/-)) mice we explored the participation of iNOS/NOS2-derived NO in heart injury in T. cruzi infection.Methodology: Rhesus monkeys and C57BL/6 and Nos2(-/-) mice were infected with the Colombian T. cruzi strain. Parasite DNA was detected by polymerase chain reaction, T. cruzi antigens and iNOS/NOS2(+) cells were immunohistochemically detected in heart sections and NO levels in serum were determined by Griess reagent. Heart injury was assessed by electrocardiogram (ECG), echocardiogram (ECHO), creatine kinase heart isoenzyme (CK-MB) activity levels in serum and connexin 43 (Cx43) expression in the cardiac tissue.Results: Chronically infected monkeys presented conduction abnormalities, cardiac inflammation and fibrosis, which resembled the spectrum of human chronic chagasic cardiomyopathy (CCC). Importantly, chronic myocarditis was associated with parasite persistence. Moreover, Cx43 loss and increased CK-MB activity levels were primarily correlated with iNOS/NOS2(+) cells infiltrating the cardiac tissue and NO levels in serum. Studies in Nos2(-/-) mice reinforced that the iNOS/NOS2-NO pathway plays a pivotal role in T. cruzi-elicited cardiomyocyte injury and in conduction abnormalities that were associated with Cx43 loss in the cardiac tissue.Conclusion: T. cruzi-infected rhesus monkeys reproduce features of CCC. Moreover, our data support that in T. cruzi infection persistent parasite-triggered iNOS/NOS2 in the cardiac tissue and NO overproduction might contribute to CCC severity, mainly disturbing of the molecular pathway involved in electrical synchrony. These findings open a new avenue for therapeutic tools in Chagas' heart disease.