Inducible nitric oxide synthase and tumor necrosis factor-alpha in myocardium in human dilated cardiomyopathy

Department of Internal Medicine II, Iwate Medical University School of Medicine, Morioka, Japan.

OBJECTIVES: We examined the mRNA expression and protein localization of inducible nitric oxide synthase (iNOS) and tumor necrosis factor-alpha (TNF-alpha) in myocardial tissue obtained from patients with dilated cardiomyopathy (DCM). BACKGROUND: The etiology of DCM is unknown, but viral infection or autoimmune abnormalities that induce cytokine expression have been proposed as pathogenetic factors. Nitric oxide (NO), synthesized by nitric oxide synthase (NOS), has negative inotropic and cytotoxic effects on cardiomyocytes. Cytokines such as TNF-alpha are potent stimulators of iNOS expression. Expression of iNOS leads to excessive production of NO in the myocardium and may modulate cardiac contractility and ventricular morphology. METHODS: We examined the mRNA expression and protein localization of iNOS and TNF-alpha in myocardial tissue obtained from 24 patients with DCM, 20 patients with hypertrophic cardiomyopathy (HCM) and 15 control subjects, using the reverse transcriptase-polymerase chain reaction method and immunohistochemical studies. We then compared the differences in clinical characteristics between DCM patient subgroups with and without myocardial iNOS expression. RESULTS: Messenger RNA expression of iNOS and TNF-alpha was observed, respectively, in 13 (54%) and 18 (75%) patients with DCM. Gene expression of TNF-alpha was consistently detected in endomyocardial tissue from patients with DCM and INOS expression. Inducible NOS protein was evident only in cardiomyocytes, whereas TNF-alpha was apparent in both cardiomyocytes and endomyocardial endothelium. Neither mRNA expression nor protein localization of iNOS or TNF-alpha was observed in cardiac tissue obtained from patients with HCM or control subjects. Patients with DCM and iNOS mRNA showed a lower left ventricular ejection fraction (p < 0.01) and a higher left ventricular volume (p < 0.05) than the negative DCM group. CONCLUSIONS: Inducible NOS was consistently coexpressed with TNF-alpha in myocardial tissue obtained from a subgroup of patients with DCM and advanced left ventricular dysfunction.

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