title: Vascular-protective effects of high-density lipoprotein include the downregulation of the angiotensin II type 1 receptor.
abstract: There is growing evidence that a cross-talk exists between the renin-angiotensin (Ang) system and lipoproteins. We investigated the role of high-density lipoprotein (HDL) on Ang II type 1 receptor (AT1R) regulation and subsequent Ang II-mediated signaling under diabetic conditions. To investigate the effect of HDL on AT1R expression in vivo, apolipoprotein A-I gene transfer was performed 5 days after streptozotocin injection. Six weeks after apolipoprotein A-I gene transfer, the 1.9-fold (P=0.001) increase of HDL cholesterol was associated with a 4.7-fold (P<0.05) reduction in diabetes mellitus-induced aortic AT1R expression. Concomitantly, NAD(P)H oxidase activity, Nox 4, and p22(phox) mRNA expression were reduced 2.6-fold, 2.0-fold, and 1.5-fold (P<0.05), respectively, whereas endothelial NO synthase dimerization was increased 3.3-fold (P<0.005). Apolipoprotein A-I transfer improved NO bioavailability as indicated by ameliorated acetylcholine-dependent vasodilation in the streptozotocin-Ad.hapoA-I group compared with streptozotocin-induced diabetes mellitus. In vitro, HDL reduced the hyperglycemia-induced upregulation of the AT1R in human aortic endothelial cells. This was associated with a 1.3-fold and 2.2-fold decreases in reactive oxygen species and NAD(P)H oxidase activity, respectively (P<0.05). Finally, HDL reduced the responsiveness to Ang II, as indicated by decreased oxidative stress in the hyperglycemia+HDL+Ang II group compared with the hyperglycemia+Ang II group. In conclusion, vascular-protective effects of HDL include the downregulation of the AT1R.
authors.affiliation: Department of Cardiology and Pneumology, Charité-University Medicine of Berlin, Campus Benjamin Franklin, Hindenburgdamm 30, 12200 Berlin, Germany.
authors.forename: Sophie
authors.initials: S
authors.lastname: Van Linthout
authors.forename: Frank
authors.initials: F
authors.lastname: Spillmann
authors.forename: Mario
authors.initials: M
authors.lastname: Lorenz
authors.forename: Marco
authors.initials: M
authors.lastname: Meloni
authors.forename: Frank
authors.initials: F
authors.lastname: Jacobs
authors.forename: Marina
authors.initials: M
authors.lastname: Egorova
authors.forename: Verena
authors.initials: V
authors.lastname: Stangl
authors.forename: Bart
authors.initials: B
authors.lastname: De Geest
authors.forename: Heinz-Peter
authors.initials: HP
authors.lastname: Schultheiss
authors.forename: Carsten
authors.initials: C
authors.lastname: Tschöpe
mesh_terms: D000804:Angiotensin II / Q000378:metabolism; D000818:Animals; D001011:Aorta / Q000502:physiology; D016632:Apolipoprotein A-I / Q000235:genetics; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism / Q000503:physiopathology; D003925:Diabetic Angiopathies / Q000378:metabolism* / Q000503:physiopathology*; D019281:Dimerization; D015536:Down-Regulation / Q000502:physiology; D004730:Endothelium, Vascular / Q000502:physiology; D018014:Gene Transfer Techniques; D006801:Humans; D006943:Hyperglycemia / Q000378:metabolism / Q000503:physiopathology; D008075:Lipoproteins, HDL / Q000378:metabolism*; D008297:Male; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases / Q000235:genetics / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000737:chemistry / Q000378:metabolism; D018384:Oxidative Stress / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D044140:Receptor, Angiotensin, Type 1 / Q000235:genetics* / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology
chemical_list: D016632:Apolipoprotein A-I; D008075:Lipoproteins, HDL; D044140:Receptor, Angiotensin, Type 1; D000804:Angiotensin II; D052250:Nitric Oxide Synthase Type III; C496316:Nos3 protein, rat; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases; C498911:Nox4 protein, rat; C515768:Cyba protein, rat