A. Sadegphour (Avtor), Michael Rappolt (Avtor), Dimitrios Ntountaniotis (Avtor), Petros Chatzigeorgioug (Avtor), Kyriakos Viras (Avtor), Grigorios Megariotis (Avtor), M. Papadopoulos (Avtor), Eleni Siapi (Avtor), Gregor Mali (Avtor), Thomas Mavromoustakos (Avtor)

Povzetek

The renin-angiotensin-aldosterone system (RAAS) plays a key role in the regulation of blood pressure. Renin is the rate limiting enzyme of the RAAS and aliskiren is a highly potent and selective inhibitor of the human renin. Renin is known to be active both in the circulating blood stream as well as locally, when bound to the (pro)-renin receptor ((P)RR). In this study we have investigated a possible mechanism of action of aliskiren, in which its accumulation in the plasma membrane is considered as an essential step for effective inhibition. Aliskiren's interactions with model membranes (cholesterol rich and poor) have been investigated by applying different complementary techniques: differential scanning calorimetry (DSC), Raman spectroscopy, magic angle spinning (MAS) nuclear magnetic resonance (NMR) spectroscopy and small- and wide-angle X-ray scattering (SAXS and WAXS). In addition, in silico molecular dynamics (MD) calculations were applied for further confirmation of the experimental data. Aliskiren's thermal effects on the pre- and main transition of dipalmitoyl-phosphatidylcholine (DPPC) membranes as well as its topographical position in the bilayer show striking similarities to those of angiotens.in II type 1 receptor (AT1R) antagonists. Moreover, at higher cholesterol concentrations aliskiren gets expelled from the membrane just as it has been recently demonstrated for the angiotensin receptor blocker (ARB) losartan. Thus, we propose that both the AT1R and the (P)RR-bound renin active sites can be efficiently blocked by membrane-bound ARBs and aliskiren when cholesterol rich membrane rafts/caveolae are formed in the vicinity of the receptors.

Ključne besede

aliskiren;renin;PRR;DPPC bilayers;raman spectroscopy;solid state NMR spectroscopy;SAXS and WAXS;MD simulations;

Podatki

Jezik: Angleški jezik
Leto izida:
Tipologija: 1.01 - Izvirni znanstveni članek
Organizacija: KI - Kemijski inštitut
UDK: 577.2
COBISS: 5618202 Povezava se bo odprla v novem oknu
ISSN: 0005-2736
Št. ogledov: 3808
Št. prenosov: 184
Ocena: 0 (0 glasov)
Metapodatki: JSON JSON-RDF JSON-LD TURTLE N-TRIPLES XML RDFA MICRODATA DC-XML DC-RDF RDF

Ostali podatki

Sekundarne ključne besede: zgradba molekule;receptorji;lipidi;
Vrsta dela (COBISS): Članek v reviji
Komentar vira: Sodelavci: M. Rappolt, D. Ntountaniotis, P. Chatzigeorgiou, K. Viras, G. Megariotis, M. G. Papadopoulos, E. Siapi, G. Mali, and T. Mavromoustakos;
Strani: str. 984-994
Letnik: ǂVol. ǂ1848
Zvezek: ǂiss. ǂ4
Čas izdaje: Apr. 2015
DOI: 10.1016/j.bbamem.2014.12.004
ID: 9145164