Role of nitric oxide and peroxynitrite in the cytokine-induced sustained myocardial dysfunction in dogs in vivo.

Studies in vitro suggested that inflammatory cytokines could cause myocardial dysfunction. However, the detailed mechanism for the cytokine-induced myocardial dysfunction in vivo remains to be examined. We thus examined this point in our new canine model in vivo, in which microspheres with and without IL-1beta were injected into the left main coronary artery. Left ventricular ejection fraction (LVEF) was evaluated by echocardiography for 1 wk. Immediately after the microsphere injection, LVEF decreased to approximately 30% in both groups. While LVEF rapidly normalized in 2 d in the control group, it was markedly impaired in the IL-1beta group even at day 7. Pretreatment with dexamethasone or with aminoguanidine, an inhibitor of inducible nitric oxide synthase, prevented the IL-1beta-induced myocardial dysfunction. Nitrotyrosine concentration, an in vivo marker of the peroxynitrite production by nitric oxide and superoxide anion, was significantly higher in the myocardium of the IL-1beta group than in that of the control group or the group cotreated with dexamethasone or aminoguanidine. There was an inverse linear relationship between myocardial nitrotyrosine concentrations and LVEF. These results indicate that IL-1beta induces sustained myocardial dysfunction in vivo and that nitric oxide produced by inducible nitric oxide synthase and the resultant formation of peroxynitrite are substantially involved in the pathogenesis of the cytokine-induced sustained myocardial dysfunction in vivo.

The correlation between the clinical laboratory data and the telomere length in peripheral blood leukocytes of Japanese female patients with hypertension.

OBJECTIVE: This study investigated the correlation between the chronological age, telomere length in peripheral blood leukocytes and blood laboratory data of female patients with mild hypertension to identify laboratory data that reflect the biological aging of individuals. DESIGN: Cross-sectional population-based study. SETTING: Outpatient clinic of the Department of Cardiovascular, Respiratory, and Geriatric Medicine Kyushu University Hospital at Beppu in Japan. PARTICIPANTS: Outpatients with mild hypertension treated with a low dose of amlodipine. MEASUREMENTS: The laboratory data of female patients were collected and the telomere length parameters in their peripheral blood leukocytes were determined by Southern blotting. Any correlations between the laboratory data and the telomere length parameters were assessed. RESULTS: The patients showed a positive correlation between the telomere length and the high density lipoprotein, albumin, creatinine, hemoglobin levels, red blood cell counts, and a negative correlation with the globulin level. The extent of subtelomeric methylation of long telomeres tended to correlate negatively with the telomeric attrition. Only the creatinine level correlated with subtelomeric methylation, but not with telomeric length. CONCLUSION: HDL and the albumin/globulin ratio were potential indicators for individual somatic genomic aging. Creatinine may therefore be a useful indicator for a predisposition for telomeric attrition.

The correlation between the telomeric parameters and the clinical laboratory data in the patients with brain infarct and metabolic disorders.

OBJECTIVE: To elucidate the correlation between the telomere length and subtelomeric methylated status in peripheral leukocytes and the laboratory data of inpatients with brain infarction and metabolic disorders. This is the first report describing a link between routine clinical laboratory data and genomic aging. DESIGN: Cross-sectional population-based study. SETTING: Chronic disease ward of Kyushu University Hospital at Beppu in Japan. PARTICIPANTS: Inpatients with brain infarction and metabolic disorders. MEASUREMENTS: The laboratory data of male patients were collected and the telomeric parameters in their peripheral leukocytes were determined by a Southern blot analysis with methylation-sensitive and insensitive isoschizomers. Any correlations between the laboratory data and the telomeric parameters were assessed. RESULTS: The patients revealed a significant correlation among the fasting blood sugar, HbA1c, serum creatinine and urea nitrogen levels with the mean telomere length, expression of long telomeres ( > 9.4 kb), or the subtelomeric hypermethylation status of long telomeres. CONCLUSION: Our results suggested that the hyperglycemia and renal function of patients with metabolic disorders correlated positively with the aging-associated telomeric changes.