endothelin-1 and Cardiovirus-Infections

Experimental autoimmune encephalitis (EAE) and virally induced demyelinating disease are two major experimental model systems used to study human multiple sclerosis. Although endothelin-1 level elevation was previously observed in the CNS of mice with EAE and viral demyelinating disease, the potential role of endothelin-1 in the development of these demyelinating diseases is unknown.. In this study, the involvement of endothelin-1 in the development and progression of demyelinating diseases was investigated using these two experimental models. Administration of endothelin-1 significantly promoted the progression of both experimental diseases accompanied with elevated inflammatory T cell responses. In contrast, administration of specific endothelin-1 inhibitors (BQ610 and BQ788) significantly inhibited progression of these diseases accompanied with reduced T cell responses to the respective antigens.. These results strongly suggest that the level of endothelin-1 plays an important role in the pathogenesis of immune-mediated CNS demyelinating diseases by promoting immune responses.

Topics: Animals; Cardiovirus Infections; Demyelinating Diseases; Endothelin-1; Female; Mice; Oligopeptides; T-Lymphocytes; Theilovirus

Renin angiotensin system contributes to activation of circulating endothelin in congestive heart failure. To investigate the effects of angiotensin II receptor antagonist and angiotensin converting enzyme inhibitors (ACEI) on the levels of endothelin-1 (ET-1), we administered orally angiotensin II type 1 receptor (AT1) antagonist, L-158,809 (ATA) (6, 1.2 and 0.12 mg/kg/day), enalapril (1 mg/kg/day) and captopril (7.5 mg/kg/day) for 14 days to mice with viral myocarditis, beginning 7 days after encephalomyocarditis virus (500 pfu/mouse) inoculation. Plasma ET-1, cardiac ET-1, heart weight (HW) and HW/ body weight (BW) ratio were examined and compared with infected untreated mice. Moreover, the HW (mg) and HW/BW (x 10(-3)) ratio were significantly (P<0.05) reduced in mice treated with ATA and ACEIs in comparison with infected control. ACEIs and higher dosed of ATA reduced myofiber hypertrophy. Both of plasma and cardiac ET-1 proteins were significantly elevated in infected control compared with uninfected normal mice. Plasma ET-1 was significantly (P<0.01) reduced in mice with three different concentrations of ATA but were not decreased in mice with captopril or enalapril compared with infected control. The expression of endothelin-1 mRNA was significantly reduced in mice with ATA in comparison with infected untreated mice by competitive RT-PCR. ATA reduced ET-1 protein and mRNA in the myocardium of mice with myocarditis, improving congestive heart failure and myofiber hypertrophy. We suggest the effect of ATA on the reduction of endothelin has a different pathway from angiotensin converting inhibitor and that ATA seems to be a useful agents for congestive heart failure due to viral myocarditis.

Topics: Angiotensin II; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Cardiovirus Infections; Encephalomyocarditis virus; Endothelin-1; Female; Mice; Mice, Inbred C3H; Myocarditis; Organ Size; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger

Serine elastases degrade elastin, stimulate vascular smooth muscle cell migration and proliferation, and are associated with myocardial damage. To evaluate the impact of elastase inhibition on cardiovascular development and disease, transgenic mice were created in which the mouse preproendothelin-1 promoter was used to target elafin overexpression to the cardiovascular system. To distinguish the transgene from endogenous elafin, constructs were made incorporating a FLAG sequence; the COOH-terminus FLAG-tagged elafin construct produced a stable, functionally active gene product and was used to create transgenic mice. Consistent with endothelin expression, abundant elafin mRNA was observed in transgenic F1 embryos (embryonic day 13.5) and in adult transgenic mice heart, trachea, aorta, kidney, lung, and skin, but not in liver, spleen, and intestine. Functional activity of the transgene was confirmed by heightened myocardial elastase inhibitory activity. No tissue abnormalities were detected by light microscopy or elastin content. However, injection of 10 plaque-forming units (PFU) of encephalomyocarditis virus resulted in death within 11 days in 10 out of 12 nontransgenic mice compared with one out of nine transgenic littermates. This reduced mortality was associated with better cardiac function and less myocardial inflammatory damage. Thus, elafin expression may confer a protective advantage in myocarditis and other inflammatory diseases.

Topics: Animals; Cardiovirus Infections; Cattle; Cells, Cultured; Disease Models, Animal; Elastin; Encephalomyocarditis virus; Endothelin-1; Endothelins; Endothelium, Vascular; Gene Expression; Humans; Mice; Mice, Transgenic; Myocarditis; Myocardium; Pancreatic Elastase; Protein Precursors; Proteinase Inhibitory Proteins, Secretory; Proteins; Pulmonary Artery; Recombinant Fusion Proteins; Serine Proteinase Inhibitors; Sheep; Tissue Distribution

Endothelin (ET) is one of the most important contributing factors in the pathophysiology of cardiovascular diseases. However, little is known about its role in myocarditis.. Four-week-old DBA/2 mice were inoculated with the encephalomyocarditis virus. Expression levels of ET-converting enzyme-1 (ECE-1) and prepro-ET-1 mRNA were significantly increased at 7 and 14 days after virus inoculation. Plasma and myocardial ET-1 levels were significantly higher in infected than noninfected mice between 5 and 14 days after virus inoculation. Immunohistochemical analyses revealed that not only endothelial cells and myocytes but also infiltrating mononuclear cells produced ET-1 protein at 7 days. Oral bosentan, a mixed ET-1 receptor antagonist, was administered after virus inoculation in doses of 0 (control group), 10, or 100 mg. kg(-1). d(-1), and the animals were killed on day 14. Mean heart weight/body weight ratios were 8.3+/-1.8 versus 11.2+/-2.4 versus 10. 8+/-2.4 in the bosentan 100 mg. kg(-1). d(-1) versus 10 mg. kg(-1). d(-1) versus control groups, respectively (P<0.05). Corresponding histological scores for myocardial necrosis were 2.0+/-0.2 versus 2. 9+/-0.3 versus 3.0+/-0.4 (P<0.05), and cellular infiltration scores were 2.3+/-0.3 versus 2.9+/-0.4 versus 3.3+/-0.4 (P<0.05). Animals killed on day 5 had significantly smaller necrotic areas after treatment with bosentan 100 mg. kg(-1). d(-1) than the group treated with a lower dose or the control group, despite the absence of differences in virus titers.. This study suggests that ET-1 plays an important pathophysiological role in viral myocarditis. Treatment with bosentan had a cardioprotective effect without modifying viral replication.

Topics: Animals; Antihypertensive Agents; Aspartic Acid Endopeptidases; Bosentan; Cardiovirus Infections; Disease Models, Animal; Encephalomyocarditis virus; Endothelin-1; Endothelin-Converting Enzymes; Endothelins; Heart; Male; Metalloendopeptidases; Mice; Mice, Inbred DBA; Myocarditis; Myocardium; Protein Precursors; RNA, Messenger; Sulfonamides