Inducible Nitric Oxide Synthase in Heart Tissue and Nitric Oxide in Serum of Trypanosoma cruzi-Infected Rhesus Monkeys: Association with Heart Injury

Abstract

BackgroundThe 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.MethodologyRhesus 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.ResultsChronically 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.

Tumor Necrosis Factor Is a Therapeutic Target for Immunological Unbalance and Cardiac Abnormalities in Chronic Experimental Chagas’ Heart Disease

“…Moreover, this model of chronic CD recapitulated ECG abnormalities and cardiac tissue injuries [18] found in chagasic patients [6] and non-human primates [23]. Similarly to CD patients [1–5], high TNF levels are detected in the serum of chronically Colombian-infected C57BL/6 mice paralleling CCC [18, 21, 25].…”

Involvement of Gap Junction Proteins in Infectious Diseases Caused by Parasites

“…The same study described a reduction of Cx43 protein levels in whole brains of T. cruzi-infected mice [47]. In monkeys, T. cruzi infection causes significant Cx43 loss in the cardiac tissue [51]. Clinical studies described that samples from chagasic patients showed alterations of cardiac Cx levels [52].…”

“…Trypanosoma cruzi Cardiomyocytes Downregulated [43] Astrocytes Downregulated [44] Leptomeningeal cells Downregulated [44] Cardiomyocytes Downregulated [48] Cardiomyocytes Downregulated [51] Cardiomyocytes and heart human biopsies Downregulated [50] Toxoplasma gondii Astrocytes Downregulated [44] Leptomeningeal cells Downregulated [44] Cx26 Toxoplasma gondii Astrocytes Downregulated [44] Cx37…”

Contribution of myeloid cell subsets to liver fibrosis in parasite infection

“…Here, we provide an overview of the mechanisms by which clinically important parasites -such as Schistosoma mansoni and S. japonicum, and hydatid cysts from Echinococcus multilocularis that localize primarily in the liverdrive liver fibrogenesis following their interaction with myeloid cell subsets. Other parasites, such as Trypanosoma cruzi , Taenia solium, Nippostrongylus brasiliensis and Schistosoma haematobium, inducing fibrosis in the heart, brain, lungs and bladder, respectively [9][10][11][12][13][14][15], and liver flukes, such as Clonorchis sinensis and Opisthorchis viverrini , causing bile periductal fibrosis, which increases the risk for cholangiocarcinoma [16][17][18][19][20], are not covered here, due to the marginal information on the phenotype, function and activation status of myeloid cells in these pathogenic processes.…”