Adenoviral Gene Transfer of SERCA2a Improves Left-Ventricular Function in Aortic-Banded Rats in Transition to Heart Failure

• Published in: Proceedings of the National Academy of Sciences - PNAS 2000-01, Vol.97 (2), p.793-798
• Main Authors: Miyamoto, Michael I., Del Monte, Federica, Schmidt, Ulrich, DiSalvo, Thomas S., Kang, Zhao Bin, Matsui, Takashi, Guerrero, J. Luis, Gwathmey, Judith K., Rosenzweig, Anthony, Hajjar, Roger J.
• Format: Article
• Language: English
• Subjects: Adenosine triphosphatases; Adenoviridae - genetics; Adenovirus; Adenoviruses; Adrenergic beta-Agonists - pharmacology; Animal models; Animals; Aorta - physiology; beta-Galactosidase - genetics; beta-Galactosidase - metabolism; Biological Sciences; Calcium; Calcium - metabolism; Calcium-Transporting ATPases - genetics; Calcium-Transporting ATPases - metabolism; Constriction; Gene Expression Regulation, Enzymologic; Gene Transfer Techniques; Genes; Green Fluorescent Proteins; Heart; Heart failure; Heart Failure - genetics; Heart Failure - physiopathology; Heart Failure - therapy; Heart rate; Heart Ventricles - pathology; Hemodynamics; Hypertrophy, Left Ventricular - genetics; Hypertrophy, Left Ventricular - physiopathology; Hypertrophy, Left Ventricular - therapy; Infections; Isoproterenol - pharmacology; Luminescent Proteins - genetics; Luminescent Proteins - metabolism; Myocardial Contraction - drug effects; Myocardium; Myocardium - cytology; Myocardium - metabolism; Proteins; Rats; Rats, Wistar; Recombinant Fusion Proteins - genetics; Recombinant Fusion Proteins - metabolism; Rodents; Sarcoplasmic Reticulum - enzymology; SERCA2 gene; Stroke Volume; Systolic pressure; Ventricular Function, Left - physiology
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.97.2.793

In human and experimental models of heart failure, sarcoplasmic reticulum Ca2+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 β -galactosidase (Ad.β gal,n=14) by using a catheter-based technique. The failing hearts infected with Ad.β gal 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 (τ). 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 (τ) 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.