title: Adenoviral gene transfer of SERCA2a improves left-ventricular function in aortic-banded rats in transition to heart failure.
abstract: In human and experimental models of heart failure, sarcoplasmic reticulum Ca(2+) ATPase (SERCA2a) activity is decreased, resulting in abnormal calcium handling. The disturbances in calcium metabolism have been shown to contribute significantly to the contractile dysfunction observed in heart failure. We investigated whether increasing SERCA2a expression can improve ventricular function in an animal model of heart failure obtained by creating ascending aortic constriction in rats. After 19-23 wk of banding during the transition from compensated hypertrophy to heart failure (documented by >25% decrease in fractional shortening), rats were randomized to receive either an adenovirus carrying the SERCA2a gene (Ad.SERCA2a, n = 13) or beta-galactosidase (Ad.betagal, n = 14) by using a catheter-based technique. The failing hearts infected with Ad. betagal were characterized by a significant decrease in SERCA2a expression and a decrease in SERCA2a activity compared with nonfailing sham-operated rats (n = 11). In addition, these failing hearts had reduced left-ventricular systolic pressure, maximal rate of left-ventricular pressure rise and decline (+dP/dt, -dP/dt), and rate of isovolumic relaxation (tau). Overexpression of SERCA2a restored both SERCA2a expression and ATPase activity to nonfailing levels. Furthermore, rats infected with Ad.SERCA2a had significant improvement in left-ventricular systolic pressure, +dP/dt, -dP/dt, and rate of isovolumic relaxation (tau) normalizing them back to levels comparable to sham-operated rats. In this study, we show that in an animal model of heart failure where SERCA2a protein levels and activity are decreased and severe contractile dysfunction is present, overexpression of SERCA2a in vivo restores both systolic and diastolic function to normal levels.
authors.affiliation: Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA 02129, USA.
authors.forename: M I
authors.initials: MI
authors.lastname: Miyamoto
authors.forename: F
authors.initials: F
authors.lastname: del Monte
authors.forename: U
authors.initials: U
authors.lastname: Schmidt
authors.forename: T S
authors.initials: TS
authors.lastname: DiSalvo
authors.forename: Z B
authors.initials: ZB
authors.lastname: Kang
authors.forename: T
authors.initials: T
authors.lastname: Matsui
authors.forename: J L
authors.initials: JL
authors.lastname: Guerrero
authors.forename: J K
authors.initials: JK
authors.lastname: Gwathmey
authors.forename: A
authors.initials: A
authors.lastname: Rosenzweig
authors.forename: R J
authors.initials: RJ
authors.lastname: Hajjar
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000818:Animals; D001011:Aorta / Q000502:physiology; D002118:Calcium / Q000378:metabolism; D000252:Calcium-Transporting ATPases / Q000235:genetics* / Q000378:metabolism; D003250:Constriction; D015971:Gene Expression Regulation, Enzymologic; D018014:Gene Transfer Techniques; D049452:Green Fluorescent Proteins; D006333:Heart Failure / Q000235:genetics / Q000503:physiopathology / Q000628:therapy*; D006352:Heart Ventricles / Q000473:pathology; D006439:Hemodynamics; D017379:Hypertrophy, Left Ventricular / Q000235:genetics / Q000503:physiopathology / Q000628:therapy*; D007545:Isoproterenol / Q000494:pharmacology; D008164:Luminescent Proteins / Q000235:genetics / Q000378:metabolism; D009200:Myocardial Contraction / Q000187:drug effects; D009206:Myocardium / Q000166:cytology / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D012519:Sarcoplasmic Reticulum / Q000201:enzymology; D013318:Stroke Volume; D016277:Ventricular Function, Left / Q000502:physiology*; D001616:beta-Galactosidase / Q000235:genetics / Q000378:metabolism
chemical_list: D000318:Adrenergic beta-Agonists; D008164:Luminescent Proteins; D011993:Recombinant Fusion Proteins; D049452:Green Fluorescent Proteins; D001616:beta-Galactosidase; D000252:Calcium-Transporting ATPases; D007545:Isoproterenol; D002118:Calcium