Published Online
on June 1, 2004

A more recent version of this article appeared on June 8, 2004

This Article Full Text (PDF) All Versions of this Article: 109/22/2780    most recent 01.CIR.0000131764.62242.96v1 Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Huq, F. Articles by Hajjar, R. J. Search for Related Content PubMed PubMed Citation Articles by Huq, F. Articles by Hajjar, R. J. Pubmed/NCBI databases Compound via MeSH Substance via MeSH Hazardous Substances DB CALCIUM COMPOUNDS CALCIUM, ELEMENTAL Medline Plus Health Information Seniors' Health Related Collections Contractile function Congestive Heart failure - basic studies Gene therapy

Submitted on June 5, 2003
Revised on January 6, 2004
Accepted on February 25, 2004

Gene Transfer of Parvalbumin Improves Diastolic Dysfunction in Senescent Myocytes

Fawzia Huq MD, Djamel Lebeche PhD, Vivek Iyer MSE, Ronglih Liao PhD, and Roger J. Hajjar MD^*

From the Cardiovascular Research Center, Massachusetts General Hospital, Harvard Medical School, Charlestown (F.H., D.L., V.I., R.J.H.), and the Cardiac Muscle Research Laboratory, Whitaker Cardiovascular Institute, Boston University School of Medicine, Boston (R.L.), Mass.

^* To whom correspondence should be addressed. E-mail: rhajjar{at}partners.org.

Background--Impaired relaxation is a cardinal feature of senescent myocardial dysfunction. Recently, adenoviral gene transfer of parvalbumin, a small calcium-buffering protein found exclusively in skeletal muscle and neurons, has been shown to improve cardiomyocyte relaxation in disease models of diastolic dysfunction. The goal of this study was to investigate whether parvalbumin gene transfer could reverse diastolic dysfunction in senescent cardiomyocytes.

Methods and Results--Myocytes were isolated from senescent (26 months) and adult (6 months) F344/BN hybrid rats and were infected with Ad.Parv.GFP (where GFP is green fluorescent protein) or Ad.gal.GFP at a multiplicity of infection of 250 for 48 hours. Uninfected senescent and adult myocytes served as controls. After stimulation at a frequency of 0.5 Hz, intracellular calcium transients and myocyte contractility were measured using dual excitation spectrofluorometry and video-edge detection system (Ionoptix). Parvalbumin significantly improved relaxation parameters in senescent myocytes: Both the rate of calcium transient decay and the rate of myocyte relengthening were dramatically increased in senescent cardiac myocytes transduced with parvalbumin compared with nontransduced and GFP-expressing controls, with no effect on myocyte shortening.

Conclusions--Parvalbumin expression corrects impaired relaxation in aging myocytes. Given that abnormalities of myocyte relaxation underlie diastolic dysfunction in a large proportion of elderly patients with heart failure, gene transfer of parvalbumin may thus be a novel approach to target diastolic dysfunction in senescent myocardium.

Key words: parvalbumin • aging • gene therapy • myocytes • diastole

This article has been cited by other articles:

				J. Davis, M. V. Westfall, D. Townsend, M. Blankinship, T. J. Herron, G. Guerrero-Serna, W. Wang, E. Devaney, and J. M. Metzger Designing Heart Performance by Gene Transfer Physiol Rev, October 1, 2008; 88(4): 1567 - 1651. [Abstract] [Full Text] [PDF]

				J. D. O'Brien, J. H. Ferguson, and S. E. Howlett Effects of ischemia and reperfusion on isolated ventricular myocytes from young adult and aged Fischer 344 rat hearts Am J Physiol Heart Circ Physiol, May 1, 2008; 294(5): H2174 - H2183. [Abstract] [Full Text] [PDF]

				S. M. Day, P. Coutu, W. Wang, T. Herron, I. Turner, M. Shillingford, N. C. LaCross, K. L. Converso, L. Piao, J. Li, et al. Cardiac-directed parvalbumin transgene expression in mice shows marked heart rate dependence of delayed Ca2+ buffering action Physiol Genomics, May 1, 2008; 33(3): 312 - 322. [Abstract] [Full Text] [PDF]

				J. L. Wilwert, N. M. Madhoun, and D. J. Coughlin Parvalbumin correlates with relaxation rate in the swimming muscle of sheepshead and kingfish J. Exp. Biol., January 15, 2006; 209(2): 227 - 237. [Abstract] [Full Text] [PDF]

				U. Schmidt, X. Zhu, D. Lebeche, F. Huq, J. L. Guerrero, and R. J. Hajjar In vivo gene transfer of parvalbumin improves diastolic function in aged rat hearts Cardiovasc Res, May 1, 2005; 66(2): 318 - 323. [Abstract] [Full Text] [PDF]