Cetirizine a histamine H1 receptor antagonist improves viral myocarditis.

BACKGROUND: We showed that mast cells played a critical role in the progression of heart failure induced by pressure overload and viral myocarditis in mice. In this study, we investigated the effect of cetirizine, a selective H1 receptor antagonist, on experimental viral myocarditis induced by encephalomyocarditis (EMC) virus. METHODS: Four-week-old inbred male DBA/2 mice were inoculated intraperitoneally with 10 plaque-forming units (pfu) of the EMC virus. Cetirizine was administered orally at a dose of 1 or 10 mg/kg per day for the survival study, and 1 mg/kg for the histologic and gene expression studies, beginning on the day of viral inoculation. RESULTS: Cetirizine improved survival dose dependently. Heart weight to body weight ratio was significantly decreased in mice treated with cetirizine. The area of myocardial necrosis was significantly smaller in the hearts of mice treated with cetirizine compared with controls. Gene expressions of tumor necrosis factor, interleukin 6, and metalloproteinase 2 were significantly suppressed in the hearts of mice treated with cetirizine. CONCLUSION: These results suggest that cetirizine exerts its beneficial effects on viral myocarditis by suppressing expression of pro-inflammatory cytokines, genes related to cardiac remodeling in the hearts of mice.

Mast cells play a critical role in the pathogenesis of viral myocarditis.

BACKGROUND: Mast cells are powerful producers of multiple cytokines and chemical mediators playing a pivotal role in the pathogenesis of various cardiovascular diseases. We examined the role of mast cells in murine models of heart failure due to viral myocarditis, using 2 strains of mast cell-deficient mice. METHODS AND RESULTS: Two strains of mast cell-deficient mice, WBB6F1-Kit(W)/Kit(W-v) (W/W(V)) and WCB6F1-Kitl(Sl)/Kitl(Sl-d) (Sl/Sl(d)), were inoculated with 10 plaque-forming units of the encephalomyocarditis virus intraperitoneally. On day 14 after inoculation, survival of W/W(V) mice was significantly higher than that of their control littermates (77% versus 31%; P=0.03; n=13). On histological examination on day 7, myocardial necrosis and cellular infiltration were significantly less pronounced in W/W(V) and Sl/Sl(d) mice than in their control littermates (area of infiltration, 7.6+/-3.5% versus 29.3+/-15.6%; P=0.002; area of necrosis, 7.6+/-3.5% versus 30.0+/-17.2%; P=0.003; n=10). Histological examination showed more severe changes in mast cell-reconstituted than in -nonreconstituted W/W(V) and Sl/Sl(d) mice. The gene expressions of mast cell proteases were upregulated in the acute phase of viral myocarditis and rose further in the subacute phase of heart failure. Their activation coincided with the development of myocardial necrosis and fibrosis and correlated with the upregulation of gene expression of matrix metalloproteinase-9. The histamine H1-receptor antagonist bepotastine improved encephalomyocarditis viral myocarditis. CONCLUSIONS: These observations suggest that mast cells participate in the acute inflammatory reaction and the onset of ventricular remodeling associated with acute viral myocarditis and that the inhibition of their function may be therapeutic in this disease.

Suppression of cytokines and nitric oxide production, and protection against lethal endotoxemia and viral myocarditis by a new NF-kappaB inhibitor.

BACKGROUND: Nuclear factor kappa B (NF-kappaB) is activated by several factors, which increase the inflammatory response, and this activation, in turn, leads to the expression of several genes such as cytokines, and may play an important role in cardiovascular diseases. AIMS: The aim of the study is to examine the effect of SUN C8079, a newly synthesized NF-kappaB inhibitor in vitro and in vivo. METHODS: We examined the effects of SUN C8079 on the transcriptional responses of NF-kappaB, on activation of NF-kappaB in electrophoretic mobility shift assay, and on the gene expressions of tumor necrosis factor (TNF)-alpha and iNOS. We also studied effects of SUN C8079 on lethal endotoxemia and viral myocarditis in mice. RESULTS: SUN C8079 inhibited the lipopolysaccharide (LPS)-induced expression of the genes of TNF-alpha and iNOS by inhibiting the activation of NF-kappaB in vitro. SUN C8079 inhibited the systemic release of TNF-alpha and improved mortality in LPS-treated mice. In addition to protecting mice against lethal endotoxemia, SUN C8079 prevented the development of myocarditis due to the encephalomyocarditis virus (EMCV), and inhibited the expressions of proinflammatory cytokines and the iNOS gene in cardiac tissues. CONCLUSION: These findings suggest that the activation of NF-kappaB plays an important role in the pathogenesis of endotoxemia and viral myocarditis, and that the NF-kappaB inhibitor, SUN C8079, may be therapeutic in these disorders.

Attenuation of virus-induced myocardial injury by inhibition of the angiotensin II type 1 receptor signal and decreased nuclear factor-kappa B activation in knockout mice.

OBJECTIVES: This study examined the role of angiotensin II (Ang-II) in a murine model of viral myocarditis. BACKGROUND: Ang-II plays an important role in the pathophysiology of various cardiovascular disorders. However, the role of Ang-II in inflammatory heart diseases is not known. METHODS: Four-week-old wild-type (WT) and Ang-II type 1 receptor (AT(1)R) knockout (KO) mice were inoculated with the encephalomyocarditis virus (EMCV). Survival, histopathology, expression of proinflammatory cytokines, and activity of nuclear factor-kappa B (NF-kB) in the heart were examined. RESULTS: The 14-day survival was significantly increased in KO compared with WT mice. Histopathologic scores for myocardial necrosis (0.86 +/- 0.69 vs. 2.44 +/- 0.88, p < 0.01) and cellular infiltration (0.86 +/- 0.38 vs. 2.33 +/- 0.50, p < 0.01) were lower in KO than in WT mice. The expression of tumor necrosis factor-alpha (TNF-alpha) was increased 43.2-fold, that of interleukin-1-beta (IL-1-beta) 45.8-fold, and the activity of NF-kB 2.24-fold by EMCV inoculation in WT mice (each p < 0.01), but not in KO mice (5.9-fold, 6.3-fold, and 1.12-fold, respectively, each p = NS). The AT(1)R blocker also significantly attenuated the expression of proinflammatory cytokines and the activation of NF-kB in virus-inoculated WT mice. Intravenous Ang-II injection enhanced the activation of NF-kB (2.28-fold, p < 0.01) and increased the expression of TNF-alpha (2.31-fold, p < 0.01) and IL-1-beta (2.45-fold, p < 0.01) in heart tissue of WT but not KO mice. CONCLUSIONS: These results indicate that the AT(1)R signal is obligatory for the development of virus-induced myocardial injury through the proinflammatory action of Ang-II via the NF-kB/cytokine pathway.

Gene expression of cardiac mast cell chymase and tryptase in a murine model of heart failure caused by viral myocarditis.

This study examined the gene expression of mouse mast cell proteases to clarify their role in the pathophysiology of viral myocarditis. Male DBA/2 mice were inoculated intraperitoneally with the encephalomyocarditis virus and the gene expression of mast cell chymase, mouse mast cell protease (mMCP)-4 and -5, and tryptase, mMCP-6, matrix metalloproteinase (MMP)-9 and type-I procollagen was measured by real-time quantitative RT-PCR analysis. The gene expression of mMCP-4, -5 and -6 mRNA was increased at 5 days, and continued to increase to day 14, coinciding with a prominent inflammatory reaction and extensive myocardial necrosis and fibrosis. The gene expression of MMP-9 was also increased, and there was a significant correlation between upregulation of mast cell proteases and MMP-9. The gene expression of type-I procollagen was increased at 5 days and continued to increase to day 14, suggesting that a fibrotic process had already begun during the acute stage of viral myocarditis. These findings suggest that mast cell chymase and tryptase participate in the acute inflammation and remodeling process of viral myocarditis.