Hypoxia-induced and high altitude pulmonary hypertension are a major problem in the mountain areas of the world. The asymmetric methylarginines (ADMA) inhibit nitric oxide (NO) synthesis by competing with L-arginine, and high levels of plasma ADMA predict adverse outcomes in pulmonary hypertension. However, little is known about the regulation of the ADMA-NO pathway in animals adapted to high altitudes. We measured the plasma ADMA concentration, endothelial NO synthase (eNOS), dimethylarginine dimethylaminohydrolases (DDAH) protein expression, and DDAH activities in the lungs from yaks. Although the yaks are hypoxemic, cardiac function and pulmonary arterial pressures are almost normal, and we found decreased DDAH expression and activity in association with reduced plasma ADMA concentrations. The eNOS expression was significantly higher in yaks. These results indicate that augmented endogenous NO activity in yaks through the ADMA-DDAH pathway and eNOS upregulation account for the low pulmonary vascular tone observed in high altitude adapted yaks.

Purpose: Muscle atrophy is a major clinical feature of chronic obstructive pulmonary disease (COPD) and is considered a predictor of mortality in COPD patients. Recently, the cross-sectional area (CSA) of the erector spinae muscles measured by chest computed tomography (CT) scans (ESM_CSA) has been reported as a clinical parameter reflecting disease severity and future prognosis in patients with COPD. In addition, the serum creatinine (Cr)/cystatin C (CysC) ratio has been considered a quantitative marker of residual muscle mass, because serum Cr levels are affected by muscle mass, and correction by CysC counteracts the effect of renal function on serum Cr levels. The purpose of this study was to assess whether the serum Cr level corrected by serum CysC can be used as a predictive marker of pulmonary function and disease severity in patients with COPD. Patients and Methods: A total of 99 patients without COPD and 201 patients with COPD, with a smoking history of more than 10 pack-years were enrolled in this study, and serum Cr and CysC levels were measured. On chest high-resolution CT images, %low attenuation area (LAA%) (≤ 960 Hounsfield units (HU)) and ESM_CSA at the Th₁₂ level were identified. Results: There was a significant correlation between the ESM_CSA and the Cr/CysC ratio. The Cr/CysC ratio was significantly associated with forced vital capacity (FVC) and forced expiratory volume in 1 second (FEV1) values, especially in former smokers. Conclusion: The serum Cr/CysC ratio could be a convenient substitute for the measurement of muscle atrophy and pulmonary function testing in patients with COPD.

Hypoxia induces the proliferation of lung fibroblasts in vivo and in vitro. However, the subcellular interactions between hypoxia and expression of tumor suppressor p53 and cyclin-dependent kinase inhibitors p21 and p27 remain unclear.

Cigarette smoke induced oxidative stress has been shown to reduce silent information regulator 1 (Sirt1) levels in lung tissue from smokers and patients with COPD patients. Sirt1 is known to inhibit endothelial senescence and may play a protective role in vascular cells. Endothelial progenitor cells (EPCs) are mobilized into circulation under various pathophysiological conditions, and are thought to play an important role in tissue repair in chronic obstructive lung disease (COPD). Therefore, Sirt1 and EPC-associated mRNAs were measured in blood samples from patients with COPD and from cultured CD34+ progenitor cells to examine whether these genes are associated with COPD development. This study included 358 patients with a smoking history of more than 10 pack-years. RNA was extracted from blood samples and from CD34+ progenitor cells treated with cigarette smoke extract (CSE), followed by assessment of CD31, CD34, Sirt1 mRNA, miR-34a, and miR-126-3p expression by real-time RT-PCR. The expression of CD31, CD34, Sirt1 mRNAs, and miR-126-3p decreased and that of miR-34a increased in moderate COPD compared with that in control smokers. However, no significant differences in these genes were observed in blood cells from patients with severe COPD compared with those in control smokers. CSE significantly decreased Sirt1 and increased miR-34a expression in cultured progenitor cells. Sirt1 expression in blood cells from patients with COPD could be a biomarker for disease stability in patients with moderate COPD. MiR-34a may participate in apoptosis and/or senescence of EPCs in smokers. Decreased expression of CD31, CD34, and miR-126-3p potentially represents decreased numbers of EPCs in blood cell from patients with COPD.