Oxidative Stress & FoxO Transcription Factors in Cardiovascular Aging.

BACKGROUND: Aging is a phenomenon in which the functions, adaptability and resistance of an organism decrease over time. With the global population aging at an accelerating pace, delaying the negative aspects of aging is vital for advancing the human life span and quality of life. The aging of multiple organs can lead to many diseases, and the cardiovascular system is no exception. Indeed, one of the primary risk factors for cardiovascular diseases is aging because of altered cardiovascular metabolism resulting in metabolic disorders and inflammation. METHODS: We attempted an organized search of bibliographic databases for peer-reviewed research papers by searching featured reviews using inclusion/exclusion criteria. The collected papers were assessed by standard tools for quality control. RESULTS: Forty-six papers were admitted to the review, and most papers featured recent research results (44) and reviewed the research field (8). We discuss these papers along with the recent progress of our work. In this review, we examine the relationship of oxidative stress with aging and the FoxO proteins, which are essential anti-aging factors in the cardiovascular system. CONCLUSION: The observations of this review suggest that anti-aging signaling mediated by FoxO proteins is important for understanding cardiovascular aging and the design of medicinal approaches.

Telomere length in circulating serum DNA as a novel non-invasive biomarker for cirrhosis: a nested case-control analysis.

BACKGROUND & AIMS: Previous studies have indicated that telomere length is associated with altered risk of various tumours including hepatitis B virus (HBV)-related hepatocellular carcinoma. However, the association between telomere length and the risk of cirrhosis has not been reported. METHODS: In this nested case-control study, we used real-time quantitative PCR to determine the relative telomere length (RTL) in serum DNA samples from 100 HBV-related cirrhosis cases and 100 frequency-matched HBV controls, and evaluated the associations between RTL and cirrhosis risk by logistic regression analyses. RESULTS: We found that cirrhotic cases had a significantly longer RTL (median, 0.36; range, 0.08-1.87) than non-cirrhotic controls (median, 0.20; range, 0.05-1.11) (P < 0.0001). Compared with subjects with short RTL, those with long RTL had a significantly increased cirrhosis risk [odds ratio, 2.76, 95% confidence interval, 1.50-5.10; P = 0.001]. Quartile analysis further indicated a dose-response effect for this association. Compared with patients with the lowest quartile of RTL, the cirrhosis risk for those with the second, third and highest quartile of RTL was 2.68 (0.91-7.87, P = 0.073), 3.37 (1.32-10.54, P = 0.013) and 6.64 (2.41-18.32, P < 0.0001) respectively (P(trend) <0.0001). Moreover, the area under the receiver operating characteristic curve increased from 0.60 (epidemiological variables) to 0.72 (epidemiological variables plus RTL), with statistically significant difference assessed by bootstrap analysis. CONCLUSIONS: Our study presents the first epidemiological evidence that RTL in serum DNA could potentially be used as a simple, inexpensive and non-invasive marker of cirrhosis risk, a finding that warrants further investigations in independent retrospective and prospective populations.

Role of LTB4 in the pathogenesis of elastase-induced murine pulmonary emphysema.

Exaggerated levels of the leukotriene B4 (LTB4) frequently coexist at sites of inflammation and tissue remodeling. Therefore, we hypothesize that the LTB4 pathway plays an important role in the pathogenesis of neutrophilic inflammation that contributes to pulmonary emphysema. In this study, significant levels of LTB4 were detected in human lung tissues with emphysema compared with lungs without emphysema (9,497 ± 2,839 vs. 4,142 ± 1,173 pg/ml, n = 9 vs. 10, P = 0.04). To further determine the biological role of LTB4 in the pathogenesis of emphysema, we compared the lungs of wild-type (WT) and LTA4 hydrolase-/- mice (LTB4 deficient, LTA4H-/-) exposed to intranasal elastase or vehicle control. We found that intranasal elastase induced accumulation of LTB4 in the lungs and caused progressively worsening emphysema between 14 and 28 days after elastase exposure in WT mice but not in LTA4H-/- mice. Premortem physiology documented increased lung compliance in elastase-exposed WT mice compared with elastase-exposed LTA4H-/- mice as measured by Flexivent (0.058 ± 0.005 vs. 0.041 ± 0.002 ml/cmH2O pressure). Postmortem morphometry documented increased total lung volume and alveolar sizes in elastase-exposed WT mice compared with elastase-exposed LTA4H-/- mice as measured by volume displacement and alveolar chord length assessment. Furthermore, elastase-exposed LTA4H-/- mice were found to have significantly delayed influx of the CD45(high)CD11b(high)Ly6G(high) leukocytes compatible with neutrophils compared with elastase-exposed WT mice. Mechanistic insights to these phenotypes were provided by demonstrating protection from elastase-induced murine emphysema with neutrophil depletion in the elastase-exposed WT mice and by demonstrating time-dependent modulation of cysteinyl leukotriene biosynthesis in the elastase-exposed LTA4H-/- mice compared with elastase-exposed WT mice. Together, these findings demonstrated that LTB4 played an important role in promoting the pathogenesis of pulmonary emphysema associated with neutrophilic pulmonary inflammation.