The role of prolylcarboxypeptidase in central blood pressure regulation

• Grant number: 12/00151-6
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• Start date: June 01, 2012
• End date: May 31, 2014
• Field of knowledge: Biological Sciences - Biochemistry - Molecular Biology
• Principal Investigator: João Bosco Pesquero
• Grantee: Ines Claudia Schadock
• Host Institution: Pró-Reitoria de Pós-Graduação e Pesquisa. Universidade Federal de São Paulo (UNIFESP). São Paulo , SP, Brazil

Abstract

Prolylcarboxypeptidase (PRCP) is an enzyme specifically cleaving the last carboxy-terminal amino acid from substrates containing a penultimate proline. Its known peptide substrates des-Arg9-bradykinin, angiotensin II (AngII) and a-melanocortin stimulating hormone (aMSH) are linked to cardiovascular phenomenon. Working with PRCP knockout (PRCP-/-) mice while my doctoral thesis, I found that these mice suffer from hypertension accompanied by left ventricular heart hypertrophy while circulating AngII and aMSH levels were unchanged. In wild type mice a high level of prcp gene expression can be found in the brain with pronounced promotor activity in cardiovascular nuclei like the paraventricular nucleus, supraoptic nucleus, nucleus tractus solitarius, and many more. These findings led to the hypothesis that PRCP might be involved in central blood pressure regulation. My postdoctoral project is conceived to prove this hypothesis. Therefore, mass spectrometrical analysis of hypothalamus and brain stem homogenates will be used to identify PRCP peptide substrates. Immunohistochemistry is planed to single out the cell populations able to produce PRCP. A better knowledge about the substrate spectrum and the enzymes exact localization will help understanding the molecular pathways the enzyme is involved. These pathways will be further examined by applying molecular biological standard methods and eventually verify candidate peptides in vivo by microinjections into mouse brains. Telemetric blood pressure recordings will parallel injections to study the physiological effects. In a second approach, blood pressure monitoring will be accompanied by pharmacological stimulation of the baroreflex to evaluate the impact of PRCP on acute blood pressure adaptations. Finally, this study should answer the question whether PRCP is a suitable target to develop novel antihypertensive drugs. (AU)