The B-type natriuretic peptide (BNP1-32) is secreted in large amounts upon increasing blood pressure and other cardiopathological conditions to protect the body by its vasoactive and antifibrotic effects. It is routinely measured in the clinic as a biomarker for the diagnosis and prognosis of heart failure and is used as a drug (Nesiritide®) for the therapy of such. In circulation, BNP1-32 is constantly exposed towards proteolytic activity and it was thus hypothesised that, similar to other vasoactive peptides, BNP1-32 is truncated forming BNP metabolites with analog or altered bioactivity, before it is degraded.Through this thesis it is possible to give a detailed overview about BNP1-32 metabolism including the discovery of different pathways and enzymes leading to the formation of a variety of BNP metabolites. The main findings are: firstly, BNP metabolism is organ-specific. Secondly, this organ-specific BNP metabolism leads to the generation of numerous different BNP metabolites, namely BNP1-31, BNP1-30, BNP1-29, BNP7-32, BNP7-31, BNP7-30, and BNP7-29. Thirdly, this generation of BNP metabolites involves a variety of different enzymes, of which one is the endothelin-converting enzyme-1 (ECE-1). Fourthly, full metabolism of BNP1-32 needs the concerted action of these enzymes. Fifthly, BNP metabolism also serves as a prerequisite for BNP clearance by neprilysin (NEP), since BNP metabolites such as BNP1-29 and BNP7-30 are degradable by the enzyme, whereas BNP1-32 is not. On the basis of these five main results, a comprehensive model of BNP processing was developed. As a sixth essential finding it was revealed that all newly identified BNP metabolites investigated exert biological activity in vitro, ex vivo, and in vivo. In particular, one of these BNP metabolites, BNP1-30, is able to reduce blood pressure substantially more strongly compared to BNP1-32 under normotensive and hypertensive conditions at least in part as a result of its altered receptor profile. The work presented shows for the first time that the metabolism of BNP1-32 is complex and involves a variety of enzymes forming different BNP metabolites with unique bioactivity and is thus representing an essential process for the cardioprotective actions of BNP. On the basis of this work it is implied that BNP processing is not purposed to generate BNP1 32 alone, but is aimed to generate BNP metabolites with similar and in part higher bioactivity compared to BNP1-32. It is thus concluded that the virtually mature BNP1-32 is rather a precursor for BNP1-30 or other BNP metabolites, a finding that suggests a fundamental revision and extension of the natriuretic peptide system. The experimental data also indicate that there might exist more metabolites of BNP, and surely also of other natriuretic peptides, exerting unique biological properties.Furthermore, the results of this thesis can be translated into clinical applications. The newly identified BNP metabolites, but also the manipulation of enzymes being involved in their formation, represent new tools for the therapy of heart failure. In particular, the metabolite BNP1 30 might be a better treatment option of cardiovascular diseases than Nesiritide®. The identification of BNP metabolites also allows the development of new diagnostic strategies in the assessment of cardiovascular diseases. In this manner, the compilation of a specific BNP metabolite profile could, as opposed to the current BNP measurement in the clinic that does not distinguish between the various forms of BNP, give detailed information about risk stratification, etiopathology, and therapeutic success.
Verknüpfung zu Publikationen oder weiteren Datensätzen
