title: Increasing HDL levels by inhibiting cholesteryl ester transfer protein activity in rabbits with hindlimb ischemia is associated with increased angiogenesis.
abstract: BACKGROUND
  High density lipoprotein (HDL) infusions increase new blood vessel formation (angiogenesis) in rodents with ischemic injury. This study asks if increasing HDL levels by inhibiting cholesteryl ester transfer protein (CETP) activity increases angiogenesis in New Zealand White (NZW) rabbits with hindlimb ischemia.
  
  
  RESULTS
  NZW rabbits were maintained for 6weeks on chow or chow supplemented with 0.07% or 0.14% (wt/wt) of the CETP inhibitor, des-fluoro-anacetrapib. The left femoral artery was ligated after 2weeks of des-fluoro-anacetrapib treatment. The animals were sacrificed 4weeks after femoral artery ligation. Treatment with 0.07% and 0.14% (wt/wt) des-fluoro-anacetrapib reduced CETP activity by 63±12% and 81±8.6%, increased plasma apoA-I levels by 1.3±0.1- and 1.4±0.1-fold, and increased plasma HDL-cholesterol levels by 1.4±0.1- and 1.7±0.2-fold, respectively. Treatment with 0.07% and 0.14% (wt/wt) des-fluoro-anacetrapib increased the number of collateral arteries by 60±16% and 84±27%, and arteriole wall area in the ischemic hindlimbs by 84±16% and 94±13%, respectively. Capillary density in the ischemic hindlimb adductor muscle increased from 1.1±0.2 (control) to 2.1±0.3 and 2.2±0.4 in the 0.07% and 0.14% (wt/wt) des-fluoro-anacetrapib-treated animals, respectively. Incubation of HDLs from des-fluoro-anacetrapib-treated animals with human coronary artery endothelial cells at apoA-I concentrations comparable with their plasma levels increased tubule network formation. These effects were abolished by knockdown of scavenger receptor-B1 (SR-B1) and PDZK1, and pharmacological inhibition of PI3K/Akt.
  
  
  CONCLUSIONS
  Increasing HDL levels by inhibiting CETP activity is associated with increased collateral blood vessel formation in NZW rabbits with hindlimb ischemia in an SR-B1- and PI3K/Akt-dependent manner.
authors.affiliation: Centre for Vascular Research, Level 3, Lowy Centre, The University of New South Wales, Sydney 2052, New South Wales, Australia; The Heart Research Institute, 7 Eliza St, Newtown, Sydney, New South Wales 2042, Australia; Sydney Medical School, University of Sydney, Sydney, New South Wales, Australia. Electronic address: ben.wu@unsw.edu.au.
authors.forename: Ben J
authors.initials: BJ
authors.lastname: Wu
authors.affiliation: Centre for Vascular Research, Level 3, Lowy Centre, The University of New South Wales, Sydney 2052, New South Wales, Australia; The Heart Research Institute, 7 Eliza St, Newtown, Sydney, New South Wales 2042, Australia.
authors.forename: Sudichhya
authors.initials: S
authors.lastname: Shrestha
authors.affiliation: Centre for Vascular Research, Level 3, Lowy Centre, The University of New South Wales, Sydney 2052, New South Wales, Australia; The Heart Research Institute, 7 Eliza St, Newtown, Sydney, New South Wales 2042, Australia; Sydney Medical School, University of Sydney, Sydney, New South Wales, Australia.
authors.forename: Kwok L
authors.initials: KL
authors.lastname: Ong
authors.affiliation: Merck & Co., Inc., Kenilworth, NJ 07033, USA.
authors.forename: Douglas
authors.initials: D
authors.lastname: Johns
authors.affiliation: The Heart Research Institute, 7 Eliza St, Newtown, Sydney, New South Wales 2042, Australia; Vascular Biology Division, Victor Chang Cardiac Research Institute, Sydney, New South Wales 2010, Australia.
authors.forename: Louise L
authors.initials: LL
authors.lastname: Dunn
authors.affiliation: Centre for Vascular Research, Level 3, Lowy Centre, The University of New South Wales, Sydney 2052, New South Wales, Australia; The Heart Research Institute, 7 Eliza St, Newtown, Sydney, New South Wales 2042, Australia.
authors.forename: Liming
authors.initials: L
authors.lastname: Hou
authors.affiliation: Centre for Vascular Research, Level 3, Lowy Centre, The University of New South Wales, Sydney 2052, New South Wales, Australia; The Heart Research Institute, 7 Eliza St, Newtown, Sydney, New South Wales 2042, Australia; Sydney Medical School, University of Sydney, Sydney, New South Wales, Australia.
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Barter
authors.affiliation: Centre for Vascular Research, Level 3, Lowy Centre, The University of New South Wales, Sydney 2052, New South Wales, Australia; The Heart Research Institute, 7 Eliza St, Newtown, Sydney, New South Wales 2042, Australia; Sydney Medical School, University of Sydney, Sydney, New South Wales, Australia. Electronic address: k.rye@unsw.edu.au.
authors.forename: Kerry-Anne
authors.initials: KA
authors.lastname: Rye
mesh_terms: D043925:Angiogenesis Inducing Agents / Q000627:therapeutic use*; D000818:Animals; D000924:Anticholesteremic Agents / Q000627:therapeutic use; D016632:Apolipoprotein A-I / Q000097:blood / Q000378:metabolism; D053480:Cholesterol Ester Transfer Proteins / Q000009:adverse effects / Q000037:antagonists & inhibitors* / Q000097:blood / Q000378:metabolism / Q000627:therapeutic use; D008076:Cholesterol, HDL / Q000097:blood / Q000378:metabolism / Q000494:pharmacology*; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D006614:Hindlimb / Q000187:drug effects / Q000473:pathology*; D006801:Humans; D007511:Ischemia / Q000188:drug therapy / Q000473:pathology*; D008075:Lipoproteins, HDL / Q000097:blood / Q000378:metabolism / Q000494:pharmacology*; D023303:Oxazolidinones / Q000627:therapeutic use; D016491:Peripheral Vascular Diseases / Q000378:metabolism / Q000473:pathology*; D019869:Phosphatidylinositol 3-Kinases / Q000097:blood / Q000378:metabolism; D011817:Rabbits
chemical_list: C505693:APOA1 protein, human; D043925:Angiogenesis Inducing Agents; D000924:Anticholesteremic Agents; D016632:Apolipoprotein A-I; D053480:Cholesterol Ester Transfer Proteins; D008076:Cholesterol, HDL; D008075:Lipoproteins, HDL; D023303:Oxazolidinones; D019869:Phosphatidylinositol 3-Kinases; C530884:anacetrapib
keywords: Angiogenesis; CETP inhibition; High density lipoproteins; Ischemia; Lipoproteins