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Rapid reversal of endothelial dysfunction in hypercholesterolemic apolipoprotein E-null mice by recombinant apolipoprotein A-I_Milano-phospholipid complex

Sanjay Kaul, MD^*,,*, Bryan Coin, BS^*,, Amir Hedayiti, MD^*,, Juliana Yano, BS^*,, Bojan Cercek, MD, PhD^*,, Kuang-Y. Chyu, MD, PhD^*, and Prediman K. Shah, MD^*,

^* Vascular Physiology and Thrombosis Research Laboratory of the Atherosclerosis Research Center, Division of Cardiology, Cedars-Sinai Medical Center, Los Angeles, California, USA
David Geffen School of Medicine, University of California, Los Angeles, California, USA

View larger version (33K): [in a new window]   Figure 1 Schema of the experimental protocols are shown. In the mice experimental protocol (A), three groups of mice were studied: normal wild-type control, untreated hypercholesterolemic (HC) apolipoprotein E-null mice (ApoE), and treated HC ApoE-null mice. The types of studies and treatment interventions are shown. See text for details of rabbit experiments (B). Apo A-IM = apolipoprotein A-IMilano; Apo A-IWT = apolipoprotein A-I wilt-type; DMPC = dimyristylphosphatidylcholine; DPPC = 1,2-dipalmitoyl-sn-3-phosphoglycerocholine; HDL = high-density lipoprotein; LDL = low-density lipoprotein; LPC = lysophosphatidylcholine.

View larger version (27K): [in a new window]   Figure 2 (A) Original tracings showing vasomotor responses in isolated descending thoracic arteries from wild-type mice (WT), untreated apo E-null mice (ApoE), and ApoE mice treated with high-dose (80 mg/kg/dose) apo A-IMilano/DPPC complex (ApoE + apo A-IM/DPPC 80) and DPPC alone (ApoE + DPPC). Dilator responses to intraluminal perfusion of endothelium-dependent agonist, acetylcholine (Ach), and endothelium-independent agonist, sodium nitroprusside (SNP) were examined in arteries preconstricted with serotonin (5-HT, 1 µM) administered abluminally. (B) Line plots showing concentration response to Ach (top panel) and sodium nitroprusside (bottom panel). Values (mean ± SEM) are percent change from a preconstricted diameter of 1.12 ± 0.02 mm. *p < 0.001 vs. ApoE, analysis of variance. Open circles = wild-type (n = 5); open triangles = ApoE + apo A-IM/DPPC 80 (n = 10); solid triangles = ApoE + apo A-IM/DPPC 20 (n = 10); open squares = ApoE + apo A-IM 80 (n = 5); solid diamonds = ApoE + DPPC (n = 5); solid circles = ApoE (n = 6).

View larger version (27K): [in a new window]   Figure 3 Bar graphs showing effects on serum total cholesterol (A) and collagen (2 µg/ml)-induced whole blood platelet aggregation (B). Platelet aggregation was measured by impedance aggregometry (Chronolog, Havertown, Pennsylvania) and data expressed as the maximal change in impedance in ohms (ohmsmax) at 6 min after the addition of collagen. Values are mean ± SEM. *p < 0.05; **p < 0.001 vs. apoliprotein E (ApoE), analysis of variance. DPPC = 1,2-dipalmitoyl-sn-3-phosphoglycerocholine; WT = wild-type.

View larger version (20K): [in a new window]   Figure 4 Bar graphs showing effects on aortic tissue cholesterol content (left panel) and acetylcholine (1 µM)-induced maximal vasodilator responses (right panel). Values are mean ± SEM. *p < 0.001 vs. apoliprotein E (ApoE); **p < 0.05 vs. ApoE, analysis of variance. A significant inverse correlation between aortic tissue cholesterol content and maximal vasodilator responses to acetylcholine was observed (Pearson's r = –0.88, p < 0.05). DPPC = 1,2-dipalmitoyl-sn-3-phosphoglycerocholine; WT = wild-type.

View larger version (39K): [in a new window]   Figure 5 Bar graphs showing concentration-dependent (upper left) and time-dependent (upper right) effects of incubation of rabbit carotid arteries with lysophosphatidylcholine (LPC) on dilator responses to acetylcholine (1 µM). The bottom panels show restoration of dilator responses after washout of 50 µM LPC (left panel) and 100 µM LPC (right panel). Values (mean ± SEM, n = 4 to 5) are percent change from a phenylephrine (1 µM)-induced preconstricted diameter of 2.0 ± 0.1 mm. *p < 0.001 vs. control; analysis of variance.

View larger version (31K): [in a new window]   Figure 6 (A) Line plots showing concentration response to acetylcholine in arteries incubated with and without lysophosphatidylcholine (LPC) (50 µM) for 30 to 45 min under different treatment conditions—control, reconstituted high-density lipoprotein (HDL) using apo A-IMilano (apo A-IM/DMPC), apo A-Iwild-type (apo A-IWT/DMPC), plasma-derived HDL, free apo A-IMilano without DMPC (apo A-IM), and DMPC alone. A concentration of 1 mg/ml based on protein was used for all preparations. The concentration of DMPC was based on a protein:phospholipid 1:3 molar ratio. (B) Bar graphs showing maximal dilator response to acetylcholine (top panel) and sodium nitroprusside (bottom panel) in rabbit carotid arteries under different treatment conditions. Values (mean ± SEM) are percent change from a preconstricted diameter of 1.9 ± 0.1 mm. p values are based on comparisons before and after incubation with LPC. Open bars = –LPC (50 µM); solid bars = +LPC (50 µM). *p < 0.005 vs. control + LPC.