Year: 2014
Type: dissertation
Abstract: Nitric oxide (NO) is one the most important and multifaceted messengers of the mammalian organism. To a large part it is synthesized by different isoforms of the NO-synthase (NOS). Under normoxia the enzyme metabolizes L-arginine to citrulline and NO with the assistance of oxygen (O2). The produced NO acts as messenger mediating neurological signals and supporting a host defense. In the cardiovascular system, NO has a great impact on vasodilation and vascular homeostasis e. g. by inhibiting platelet activation. Under hypoxia and ischemia this sensitive system is impaired, as the needed cofactor O2 is deficient. A back-up system partly compensates the emerging lack of endogenous NO, by way of NO synthesis. Gaseous NO has a short half-life and is fast oxidized to nitrite (NO2-) and further to nitrate (NO3-). These circulating metabolites could be reduced back to NO by e. g. myoglobin, hemoglobin, and cytoglobin whereby, on the whole NO3- is reduced to NO2- by commensal oral bacteria. Without O2, these enzymes switch from e. g. NO-scavengers to NO producing molecules absorbing reduced endogenous NO synthesis. However, NO2- and NO3- are not only endogenously produced. Both are ingredients of several foods. These ingested inorganic NO2- and NO3- also fill up the pool of reducible NO metabolites. Hence, recent works could show that an increase in dietary NO3- (and NO2-) not only increases the endogenous NO3- (NO2-) pool, but could also improve regeneration after ischemia. These works, in combination with novel considerations referring the toxicity of NO2- and NO3- resulted in a new perception of these nutritional ingredients with relativization of hazardous effects and more emphasis on its beneficial potential. The current study hypothesized that supplementation with dietary NO3- improves regeneration in the murine hind limb model, an animal model of peripheral ischemia. It is supposed that regeneration is supported by revascularization, increased mobilization of Endothelial-regenerating cells and increased muscle tissue protection. Finally, it is proposed that the decrease in NO production and the subsequent decreased endothelial regenerating cell level is associated with a severe cardiovascular disease, such as the myocardial infarction. Accordingly, present work demonstrates that the increase of bioavailable NO by dietary NO3- increases perfusion of affected tissue elucidating its regenerative potential. It could be shown that mobilization and migration of Endothelial-regenerating cells is significantly improved. Moreover, it shows that not only revascularization but also tissue protection is improved. It is proposed that this cytoprotection is mediated by Endothelial-regenerating cells with the Fas/FasL pathway, as candidate for paracrine reactions. Indeed, the work in hand shows that Endothelial-regenerating cells express FasL modulated by NO3- intake. Presented clinical studies corroborate the hypothesis of decreased NO bioavailability in myocardial infarction with associative relation to its severity. In conclusion, it could be demonstrated that dietary NO3- acts cytoprotective in the ischemic hind limb model, mediating mobilization and migration of endothelial-regenerating cells. Description of decreased NO bioavailability in myocardial infarction underscores the importance of increasing NO level in (cardio)vascular disease. The relevance of the beneficial potential of the NO3- NO2- NO pathway is supported, highlighting the impact of dietary NO3- in ischemia.
Source: RWTH Publications (RWTH Aachen)
Authors: Martina Kropp, H. N. Wagner
Language: English
Subfield: Physiology (medical)
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W2279476808