Sources and Consequences of Reactive Oxygen Species in Right Ventricular Hypertrophy and Right Ventricular Failure

Paulus, W.J. [Promotor]Simonides, W.S. [Copromotor]Musters, R.J.P. [Copromotor

Protective effects of hydrogen-rich saline on monocrotaline-induced pulmonary hypertension in a rat model

<p>Abstract</p> <p>Background</p> <p>Hydrogen-rich saline has been reported to have antioxidant and anti-inflammatory effects and effectively protect against organ damage. Oxidative stress and inflammation contribute to the pathogenesis and/or development of pulmonary hypertension. In this study, we investigated the effects of hydrogen-rich saline on the prevention of pulmonary hypertension induced by monocrotaline in a rat model.</p> <p>Methods</p> <p>In male Sprague-Dawley rats, pulmonary hypertension was induced by subcutaneous administration of monocrotaline at a concentration of 6 mg/100 g body weight. Hydrogen-rich saline (5 ml/kg) or saline was administred intraperitoneally once daily for 2 or 3 weeks. Severity of pulmonary hypertension was assessed by hemodynamic index and histologic analysis. Malondialdehyde and 8-hydroxy-desoxyguanosine level, and superoxide dismutase activity were measured in the lung tissue and serum. Levels of pro-inflammatory cytokines (tumor necrosis factor-α, interleukin-6) in serum were determined with enzyme-linked immunosorbent assay.</p> <p>Results</p> <p>Hydrogen-rich saline treatment improved hemodynamics and reversed right ventricular hypertrophy. It also decreased malondialdehyde and 8-hydroxy-desoxyguanosine levels, and increased superoxide dismutase activity in the lung tissue and serum, accompanied by a decrease in pro-inflammatory cytokines.</p> <p>Conclusions</p> <p>These results suggest that hydrogen-rich saline ameliorates the progression of pulmonary hypertension induced by monocrotaline in rats, which may be associated with its antioxidant and anti-inflammatory effects.</p

Pressure Load: The Main Factor for Altered Gene Expression in Right Ventricular Hypertrophy in Chronic Hypoxic Rats

BACKGROUND: The present study investigated whether changes in gene expression in the right ventricle following pulmonary hypertension can be attributed to hypoxia or pressure loading. METHODOLOGY/PRINCIPAL FINDINGS: To distinguish hypoxia from pressure-induced alterations, a group of rats underwent banding of the pulmonary trunk (PTB), sham operation, or the rats were exposed to normoxia or chronic, hypobaric hypoxia. Pressure measurements were performed and the right ventricle was analyzed by Affymetrix GeneChip, and selected genes were confirmed by quantitative PCR and immunoblotting. Right ventricular systolic blood pressure and right ventricle to body weight ratio were elevated in the PTB and the hypoxic rats. Expression of the same 172 genes was altered in the chronic hypoxic and PTB rats. Thus, gene expression of enzymes participating in fatty acid oxidation and the glycerol channel were downregulated. mRNA expression of aquaporin 7 was downregulated, but this was not the case for the protein expression. In contrast, monoamine oxidase A and tissue transglutaminase were upregulated both at gene and protein levels. 11 genes (e.g. insulin-like growth factor binding protein) were upregulated in the PTB experiment and downregulated in the hypoxic experiment, and 3 genes (e.g. c-kit tyrosine kinase) were downregulated in the PTB and upregulated in the hypoxic experiment. CONCLUSION/SIGNIFICANCE: Pressure load of the right ventricle induces a marked shift in the gene expression, which in case of the metabolic genes appears compensated at the protein level, while both expression of genes and proteins of importance for myocardial function and remodelling are altered by the increased pressure load of the right ventricle. These findings imply that treatment of pulmonary hypertension should also aim at reducing right ventricular pressure

Right-ventricular failure is associated with increased mitochondrial complex II activity and production of reactive oxygen species.

Objective: Reactive oxygen species (ROS) have been implicated in the progression of ventricular hypertrophy to congestive heart failure. However, the source of increased oxidative stress in cardiomyocytes remains unclear. Methods: Here we examined NADPH oxidase and mitochondria as sources of ventricular ROS production in a rat model of right-ventricular (RV) failure (CHF) induced by pulmonary arterial hypertension (PAH). Results: Western analysis showed increased expression of the catalytic subunit gp9