title: Comparative study of interactions of aliskiren and AT1 receptor antagonists with lipid bilayers.
abstract: 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 angiotensin 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.
authors.affiliation: School of Food Science & Nutrition, University of Leeds, Leeds LS2 9JT, UK.
authors.forename: A
authors.initials: A
authors.lastname: Sadeghpour
authors.affiliation: School of Food Science & Nutrition, University of Leeds, Leeds LS2 9JT, UK. Electronic address: m.rappolt@leeds.ac.uk.
authors.forename: M
authors.initials: M
authors.lastname: Rappolt
authors.affiliation: Chemistry Department of National Kapodistrian University, Zografou, Athens 15784, Greece.
authors.forename: D
authors.initials: D
authors.lastname: Ntountaniotis
authors.affiliation: Chemistry Department of National Kapodistrian University, Zografou, Athens 15784, Greece.
authors.forename: P
authors.initials: P
authors.lastname: Chatzigeorgiou
authors.affiliation: Chemistry Department of National Kapodistrian University, Zografou, Athens 15784, Greece.
authors.forename: K
authors.initials: K
authors.lastname: Viras
authors.affiliation: National Hellenic Research Foundation, Institute of Biology, Medicinal Chemistry& Biotechnology, Vas. Constantinou 48, 11635 Athens, Greece.
authors.forename: G
authors.initials: G
authors.lastname: Megariotis
authors.affiliation: National Hellenic Research Foundation, Institute of Biology, Medicinal Chemistry& Biotechnology, Vas. Constantinou 48, 11635 Athens, Greece.
authors.forename: M G
authors.initials: MG
authors.lastname: Papadopoulos
authors.affiliation: National Hellenic Research Foundation, Institute of Biology, Medicinal Chemistry& Biotechnology, Vas. Constantinou 48, 11635 Athens, Greece.
authors.forename: E
authors.initials: E
authors.lastname: Siapi
authors.affiliation: Laboratory for Inorganic Chemistry and Technology, National Institute of Chemistry, Hajdrihova 19, SI-1001 Ljubljana, Slovenia.
authors.forename: G
authors.initials: G
authors.lastname: Mali
authors.affiliation: Chemistry Department of National Kapodistrian University, Zografou, Athens 15784, Greece. Electronic address: tmavrom@chem.uoa.gr.
authors.forename: T
authors.initials: T
authors.lastname: Mavromoustakos
mesh_terms: D015060:1,2-Dipalmitoylphosphatidylcholine / Q000378:metabolism*; D000577:Amides / Q000378:metabolism*; D047228:Angiotensin II Type 1 Receptor Blockers / Q000378:metabolism*; D002152:Calorimetry, Differential Scanning; D020134:Catalytic Domain; D021941:Caveolae / Q000378:metabolism; D002462:Cell Membrane / Q000378:metabolism*; D002784:Cholesterol / Q000378:metabolism; D005650:Fumarates / Q000378:metabolism*; D006801:Humans; D008051:Lipid Bilayers / Q000378:metabolism*; D021962:Membrane Microdomains / Q000378:metabolism; D012083:Renin / Q000378:metabolism*; D053838:Scattering, Small Angle; D013059:Spectrum Analysis, Raman; D014961:X-Ray Diffraction; D000092502:Renin Inhibitors
chemical_list: D015060:1,2-Dipalmitoylphosphatidylcholine; D000577:Amides; D047228:Angiotensin II Type 1 Receptor Blockers; D002784:Cholesterol; D005650:Fumarates; D008051:Lipid Bilayers; D012083:Renin; D000092502:Renin Inhibitors; C446481:aliskiren
keywords: Aliskiren; DPPC bilayer; PRR; Renin