title: SERCA2a gene transfer enhances eNOS expression and activity in endothelial cells.
abstract: Congestive heart failure (HF) is associated with impaired endothelium-dependent nitric oxide-mediated vasodilatation. The aim of this study was to examine the effects of sarco/endoplasmic reticulum (ER) Ca(2+)-ATPase 2a (SERCA2a) gene transfer on endothelial function in a swine HF model. Two months after the creation of mitral regurgitation to induce HF, the animals underwent intracoronary injection of adeno-associated virus (AAV) carrying SERCA2a (n = 7) or saline (n = 6). At 4 months, coronary flow (CF) was measured in the mid-portion of the left anterior descending (LAD) artery. In the failing animals, CF was decreased significantly; SERCA2a gene transfer rescued CF to levels observed in sham-group [ml/min/g, 0.47 +/- 0.064 saline versus 0.89 +/- 0.116, SERCA2a; P < 0.05; 1.00 +/- 0. 185 sham P = NS (nonsignificant)]. In coronary arteries from HF animals, SERCA2a and endothelial isoform of nitric oxide synthase (eNOS) protein expression were decreased, but restored to normal levels by SERCA2a gene transfer. In human coronary artery endothelial cells (HCAECs), SERCA2a overexpression increased eNOS expression, phosphorylation, eNOS promoter activity, Ca(2+) storage capacity, and enhanced histamine-induced calcium oscillations, eNOS activity, and cyclic guanosine monophosphate (cGMP) production. Thus, SERCA2a gene transfer increases eNOS expression and activity by modulating calcium homeostasis to improve CF. These findings suggest that SERCA2a gene transfer improves vascular reactivity in the setting of HF.
authors.affiliation: Cardiovascular Research Center, Mount Sinai School of Medicine, New York, New York 10029, USA.
authors.forename: Lahouaria
authors.initials: L
authors.lastname: Hadri
authors.forename: Regis
authors.initials: R
authors.lastname: Bobe
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Kawase
authors.forename: Dennis
authors.initials: D
authors.lastname: Ladage
authors.forename: Kiyotake
authors.initials: K
authors.lastname: Ishikawa
authors.forename: Fabrice
authors.initials: F
authors.lastname: Atassi
authors.forename: Djamel
authors.initials: D
authors.lastname: Lebeche
authors.forename: Evangelia G
authors.initials: EG
authors.lastname: Kranias
authors.forename: Jane A
authors.initials: JA
authors.lastname: Leopold
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: Lompré
authors.forename: Larissa
authors.initials: L
authors.lastname: Lipskaia
authors.forename: Roger J
authors.initials: RJ
authors.lastname: Hajjar
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002460:Cell Line; D003331:Coronary Vessels / Q000166:cytology; D042783:Endothelial Cells / Q000378:metabolism*; D005260:Female; D018014:Gene Transfer Techniques; D006333:Heart Failure / Q000378:metabolism / Q000628:therapy; D006801:Humans; D047468:Immunoprecipitation; D018613:Microscopy, Confocal; D052250:Nitric Oxide Synthase Type III / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000235:genetics / Q000378:metabolism*; D013552:Swine
chemical_list: D052250:Nitric Oxide Synthase Type III; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases
references.citation: J Physiol. 2000 May 1;524 Pt 3:701-13
references.pmid: 10790152
references.citation: J Am Coll Cardiol. 2008 Mar 18;51(11):1112-9
references.pmid: 18342232
references.citation: Nat Clin Pract Cardiovasc Med. 2008 Sep;5(9):554-65
references.pmid: 18665137
references.citation: FEBS Lett. 1998 Nov 27;440(1-2):218-22
references.pmid: 9862458
references.citation: Circulation. 2003 May 13;107(18):2348-54
references.pmid: 12707234
references.citation: Clin Exp Pharmacol Physiol. 1996 Aug;23(8):715-21
references.pmid: 8886496
references.citation: Proc Natl Acad Sci U S A. 2000 Jan 18;97(2):793-8
references.pmid: 10639159
references.citation: Circulation. 1999 Jul 20;100(3):292-8
references.pmid: 10411855
references.citation: Circ Res. 2000 May 26;86(10):1085-92
references.pmid: 10827139
references.citation: Circ Res. 2005 Sep 2;97(5):488-95
references.pmid: 16081870
references.citation: Nat Methods. 2006 May;3(5):331
references.pmid: 16628201
references.citation: Circ Res. 2003 May 30;92(10):1115-22
references.pmid: 12730091
references.citation: J Biol Chem. 2002 Sep 27;277(39):36471-8
references.pmid: 12119294
references.citation: Proc Natl Acad Sci U S A. 2004 Apr 13;101(15):5622-7
references.pmid: 15044708
references.citation: Hypertension. 1997 Jul;30(1 Pt 1):50-6
references.pmid: 9231820
references.citation: Circulation. 2004 Jun 8;109(22):2780-5
references.pmid: 15173024
references.citation: J Am Coll Cardiol. 1998 Nov;32(5):1179-86
references.pmid: 9809923
references.citation: J Biol Chem. 2000 Dec 29;275(52):40732-41
references.pmid: 11013235
references.citation: Cardiovasc Res. 1997 Sep;35(3):514-21
references.pmid: 9415296
references.citation: J Biol Chem. 2003 Nov 21;278(47):46230-40
references.pmid: 12963737
references.citation: Circ Res. 2008 Apr 11;102(7):786-94
references.pmid: 18292599
references.citation: J Mol Cell Cardiol. 2007 Apr;42(4):852-61
references.pmid: 17300800
references.citation: Lancet. 2004 Apr 24;363(9418):1365-7
references.pmid: 15110495
references.citation: Platelets. 2005 May-Jun;16(3-4):133-50
references.pmid: 16011958
references.citation: Am Heart J. 1993 Sep;126(3 Pt 2):761-4
references.pmid: 8362750
references.citation: Hypertension. 2001 Jan;37(1):135-141
references.pmid: 11208768
references.citation: Expert Opin Biol Ther. 2010 Jan;10(1):29-41
references.pmid: 20078230
references.citation: J Immunol. 1999 Oct 1;163(7):3758-63
references.pmid: 10490972
references.citation: Circulation. 1990 Mar;81(3):772-9
references.pmid: 2306829
references.citation: Circulation. 1991 Oct;84(4):1589-96
references.pmid: 1914099
references.citation: Mol Ther. 2006 May;13(5):987-96
references.pmid: 16503203
references.citation: Am J Physiol Regul Integr Comp Physiol. 2003 Jan;284(1):R1-12
references.pmid: 12482742
references.citation: Nat Clin Pract Cardiovasc Med. 2008 Dec;5(12):749
references.pmid: 19023329
references.citation: Am J Physiol. 1994 Feb;266(2 Pt 2):H670-80
references.pmid: 8141368
references.citation: Circulation. 2001 Sep 18;104(12):1424-9
references.pmid: 11560860
references.citation: Circ Res. 1996 Jan;78(1):58-64
references.pmid: 8603506
references.citation: Am J Physiol Heart Circ Physiol. 2007 Feb;292(2):H1204-7
references.pmid: 17012346
references.citation: Circulation. 1995 May 15;91(10):2655-63
references.pmid: 7743629
references.citation: Biochem J. 1990 Nov 1;271(3):649-53
references.pmid: 2244871