Upregulation of DDAH2 Limits Pulmonary Hypertension and Right Ventricular Hypertrophy During Chronic Hypoxia in Ddah1 Knockout Mice.

Objective: Chronic hypoxia causes pulmonary vasoconstriction leading to pulmonary hypertension and right ventricular hypertrophy. Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of nitric oxide (NO) synthesis; its level increases in hypoxia (HX) concomitantly with reduced activity of dimethylarginine dimethylaminohydrolases (DDAH-1 and DDAH-2), enzymes metabolizing ADMA. Ddah1 knockout (KO) mice may therefore help to understand the pathophysiological roles of this enzyme and its substrate, ADMA, in the development of hypoxia-associated pulmonary hypertension. Methods: Ddah1 KO mice and their wild-type (WT) littermates were subjected to normoxia (NX) or for 21 days. We measured ADMA concentration in plasma and lungs, DDAH1 and DDAH2 mRNA and protein expression in the lungs, right ventricular systolic pressure (RVSP), right ventricular hypertrophy by the Fulton index, and cardiomyocyte hypertrophy by dystrophin staining of the heart. Results: Ddah1 KO mice had higher ADMA concentrations in plasma and in lung tissue than WT in NX (p < 0.05). ADMA significantly increased in WT-HX in plasma and lungs, while there were no significant differences in WT-HX vs. KO-HX. This finding was paralleled by a 38 ± 13% reduction in Ddah1 but not Ddah2 mRNA expression, and reduced DDAH1 protein expression but stable DDAH2 protein levels in WT mice. Ddah1 KO mice showed significant elevation of DDAH2 protein but not mRNA levels, which further increased in HX. HX led to increased RVSP and right ventricular hypertrophy in both, WT and KO mice, with no significant differences between both genotypes. Conclusions: Chronic hypoxia causes an elevation of ADMA, which may impair NO production and lead to endothelial dysfunction and vasoconstriction. Downregulation of DDAH1 expression and activity may be involved in this; however, knockout of the Ddah1 gene does not modify the hypoxia-induced pathophysiological changes of pulmonary blood pressure and right ventricular hypertrophy, possibly due to compensatory upregulation of DDAH2 protein.

Exploratory analysis of the neutrophil to lymphocyte ratio in patients with pulmonary arterial hypertension.

BACKGROUND: Chronic inflammation emerges as a feature of the pathogenesis of pulmonary arterial hypertension (PAH) in experimental models. Alterations of circulating cell subsets have been observed in patients with PAH. We aimed to assess associations of the white blood cell count with disease severity and outcome in patients with PAH. METHODS: The total and differential white blood cell count was related to functional parameters, pulmonary hemodynamics and transplantation-free survival in 77 patients with PAH in an observational single center study. RESULTS: An increased neutrophil/lymphocyte ratio was associated with poor World Health Organization functional class and shorter 6-minute walking distance, as well as with elevated right atrial pressure and high level of N-terminal prohormone of brain natriuretic peptide. During a median follow-up period of 31 months (range 16-56) 23 patients died and 2 patients were referred to lung transplantation. Using uni- and subsequent bivariate Cox proportional hazards analyses an increased neutrophil/lymphocyte ratio was associated with unfavorable transplantation-free survival independent of hemodynamic parameters and C-reactive protein. The prognostic implication sustained in subsets of patients with incident PAH and in the absence of cardiovascular risk factors. CONCLUSIONS: The results of this analysis indicate that a neutrophilic inflammation may be associated with clinical deterioration and poor outcome in patients with PAH. Assessing the composition of the differential white blood cell count may render prognostic information and could represent a step towards incorporating an inflammatory marker into the clinical management of patients with PAH.

Acute effects of exercise on the inflammatory state in patients with idiopathic pulmonary arterial hypertension.

BACKGROUND: Exercise training positively influences exercise tolerance and functional capacity of patients with idiopathic pulmonary arterial hypertension (IPAH). However, the underlying mechanisms are unclear. We hypothesized that exercise modulates the activated inflammatory state found in IPAH patients. METHODS: Single cardiopulmonary exercise testing was performed in 16 IPAH patients and 10 healthy subjects. Phenotypic characterization of peripheral blood mononuclear cells and circulating cytokines were assessed before, directly after and 1 h after exercise. RESULTS: Before exercise testing, IPAH patients showed elevated Th2 lymphocytes, regulatory T lymphocytes, IL-6, and TNF-alpha, whilst Th1/Th17 lymphocytes and IL-4 were reduced. In IPAH patients but not in healthy subject, exercise caused an immediate relative decrease of Th17 lymphocytes and a sustained reduction of IL-1-beta and IL-6. The higher the decrease of IL-6 the higher was the peak oxygen consumption of IPAH patients. CONCLUSIONS: Exercise seems to be safe from an immune and inflammatory point of view in IPAH patients. Our results demonstrate that exercise does not aggravate the inflammatory state and seems to elicit an immune-modulating effect in IPAH patients.