Adenosine thiamine triphosphate (AThTP) inhibits poly(ADP-ribose) polymerase-1 (PARP-1) activity.

Overactivation of poly(ADP-ribose) polymerase-1 (PARP-1) has been demonstrated to result in various stress-related diseases, including diabetes mellitus. Deficiency of cellular nicotinamide adenine dinucleotide (NAD(+)) content, consumed by PARP-1 to add ADP-ribose moieties onto target proteins, contributes to pathophysiological conditions. Adenosine thiamine triphosphate (AThTP) exists in small amounts in mammals; however, the function(s) of this metabolite remains unresolved. The structure of AThTP resembles NAD(+). Recent experimental studies demonstrate beneficial impacts of high-dose thiamine treatment of diabetic complications. These findings have led us to hypothesize that AThTP may modulate the activity of PARP-1. We have chemically synthesized AThTP and evaluated the effect of AThTP on recombinant PARP-1 enzyme activity. AThTP inhibited the PARP-1 activity at 10 µM, and a structural model of the PARP-1-AThTP complex highlighted the AThTP binding site. The results provide new insights into the pharmacological importance of AThTP as an inhibitor of PARP-1.

Evidence of viral infection in the myocardium of American and Japanese patients with idiopathic dilated cardiomyopathy.

Enteroviruses have been implicated in the pathogenesis of idiopathic dilated cardiomyopathy (IDC). Recently, the association of adenovirus or parvovirus with IDC has been reported. Viral infection in the myocardium of American and Japanese patients with end-stage IDC was evaluated. Myocardial specimens from 30 American patients with IDC and 47 Japanese patients with IDC were analyzed for the presence of cardiotropic viruses. The strand-specific detection of enteroviral ribonucleic acid (RNA) was performed to determine viral activity in hearts with IDC. Established reverse transcription-polymerase chain reaction (PCR) or PCR techniques were used to detect genomic sequences of influenza viruses, mumps virus, adenovirus, parvovirus, herpes simplex viruses, varicella-zoster virus, and Epstein-Barr virus. Enteroviral RNA was detected in 7 of the 30 American patients (23%) and in 15 of the 47 Japanese patients (32%). Minus-strand enteroviral RNA, an indicator of active enteroviral RNA replication, was demonstrated in 5 of 7 plus-strand-positive American patients (71%) and in 12 of 15 plus-strand-positive Japanese patients (80%). Sequence analysis revealed that the viruses detected were Coxsackie B viruses. No genomic sequences of other viruses were detected in the myocardium of either American or Japanese patients with IDC. Therefore, active group B Coxsackie virus RNA replication in the myocardium was demonstrated in a significant proportion of American and Japanese patients with end-stage IDC. There was no evidence of persistent infection by other viruses in hearts with IDC. Specific therapy should be designed for Coxsackie virus positive patients with IDC.

[Influenza myocarditis--pathophysiology and developmental mechanism of myocarditis].

Acute myocarditis is a rare complication in influenza infection, but it is serious and occasionally fatal. Recent application of intraaortic balloon pumping(IABP) and/or percutaneous cardiopulmonary support(PCPS) to the serious cases of viral myocarditis brought a better prognosis. We should recognize that the patient with viral infection such as influenza infection may have acute myocarditis and should make an early diagnosis for adequate treatment in time. To avoid misdiagnosis of acute myocarditis complicated with influenza infection, we must know characteristic symptoms, signs and laboratory findings of acute myocarditis during influenza infection. The mechanism of cardiocyte injury in experimental influenza myocarditis of mice is also discussed.

Quantitative analysis of cytokine mRNA expression in hearts from patients with nonischemic dilated cardiomyopathy (DCM).

PURPOSE AND METHODS: There is increasing evidence that inflammatory cytokines play an important role in the development of heart failure. To evaluate the role of cytokines in nonischemic DCM, we analyzed the relative quantity of cytokine mRNA expression in the hearts from DCM patients with refractory heart failure, using the ABI PRISM7700 real-time PCR system. We used heart tissues resected from 32 DCM patients at the time of elective partial ventriculectomy (PLV), and five biopsy specimens with normal histological findings as control. RESULTS AND DISCUSSION: Interleukin (IL)-1beta, IL-10, and Tumor Necrosis Factor (TNF)-alpha mRNA were expressed at low levels in all normal hearts. The number of IL-10-positive DCM cases was significantly smaller than normal controls (P = 0.0036). One (10%) of 10 DCM patients with IL-10 mRNA expression died after PLV, and 10 (45%) of 22 DCM patients without IL-10 mRNA expression died. IL-1beta mRNA was overexpressed (over twice the mean of control subjects) in 15 of 32, and TNF-alpha mRNA in 10 of 32 patients. We propose the classification of DCM patients into subgroups on the basis of cytokine mRNA expression. Anticytokine therapy or cytokine therapy may have potential in improving the condition of heart failure in certain subgroups of DCM patients. CONCLUSIONS: We suggest that DCM patients with heart failure deteriorate without IL-10 mRNA expression in the myocardium. The classification of DCM patients into subgroups on the basis of cytokine mRNA expression may have great value in considering the treatment of this heterogeneous disease state.

Immunologic interaction between infiltrating eosinophils and T lymphocytes in murine spontaneous eosinophilic myocarditis.

BACKGROUND: Eosinophilic myocarditis often occurs spontaneously in DBA/2 mice. Relationships between infiltrating eosinophils (Eos), T lymphocytes and interleukin-5 (IL-5) in this disorder were investigated microscopically and immunohistochemically. METHODS: Hearts from male DBA/2 mice were studied from 5 to 10 weeks of age. Anti-CD4 and anti-CD8 antibodies were used. Infiltrating Eos, white blood cells (WBC), and CD4+ and CD8+ T cells were counted. Interactions were assessed with multiple regression and forward stepwise regression tests. Additionally, IL-5 distribution in heart tissue was histologically observed with special reference to immunological findings. RESULTS: Beginning at 5 weeks, several necrotic foci containing many damaged cardiocytes were seen in the epicardium of the right ventricle. Eos and lymphocytes were numerous within and around the necrotic foci. Eos were occasionally seen adjacent to degenerating cardiocytes. Three quarters of the mice exhibited such Eo-related myocardial damage. CD4+ lymphocytes were often seen infiltrating actively inflamed foci where Eos could also be observed. The lesional CD4+-to-CD8+ ratio (CD4/CD8) was 5.2 +/- 3.3 at 6 weeks, 6.8 +/- 3.7 at 7 weeks, and 1.5 +/- 0.8 at 10 weeks of age. The lesional Eo/WBC ratio was directly proportional to the CD4/CD8 ratio (p < 0.05), and was also significantly related to lesional CD4+ T cell count (p < 0.05). IL-5 was also expressed in Eo-rich areas. CONCLUSIONS: In this mouse strain with susceptibility to eosinophilic myocarditis, Eo infiltration was related to increased lesional CD4+ cell count. We suspect that CD4+ T cells induce local eosinotaxis, mediated by IL-5, and participate in myocardiocyte injury via Eo induction.