In vivo gene transfer of parvalbumin improves diastolic function in aged rat hearts.
OBJECTIVE
Diastolic dysfunction is a characteristic finding of the aged mammalian heart. Parvalbumin acts as a Ca2+ sink and enhances relaxation in skeletal muscle, and overexpression of parvalbumin in myocardium increased cardiac relaxation in vitro as well as in vivo. Therefore, the objective of this study is to test the hypothesis that in vivo gene transfer of parvalbumin will improve diastolic dysfunction in aged rat heart.


METHODS
We used adenovirus to transfer parvalbumin into two different rat models of aging: the Fischer 344 (F344) and the Fischer 344 x Brown Norway F1 hybrid (F344 x BN). Cardiac function was measured and compared after gene transfer.


RESULTS
In vivo overexpression of parvalbumin in both rat aging models had no effect on systolic parameters but reduced left ventricular diastolic pressure and the time course of pressure decline. Overexpression of parvalbumin also improved the force frequency relationship in senescent rats.


CONCLUSIONS
In vivo overexpression of parvalbumin improves diastolic dysfunction in two rat models of senescence, and this effect is independent of the rat strain investigated. The results show promise that gene therapy of parvalbumin may address the impaired Ca2+ homeostasis and diastolic dysfunction without an increase in energy expenditure.
Schmidt
Ulrich
U
Department of Anesthesia and Critical Care, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
Zhu
Xinsheng
X
Lebeche
Djamel
D
Huq
Fawzia
F
Guerrero
J Luis
JL
Hajjar
Roger J
RJ
D000256:Adenoviridae / Q000235:genetics; D000375:Aging / Q000502:physiology*; D000818:Animals; D000252:Calcium-Transporting ATPases / Q000378:metabolism; D003971:Diastole; D005818:Genetic Engineering; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000008:administration & dosage; D006706:Homeostasis; D008297:Male; D023421:Models, Animal; D009206:Myocardium / Q000378:metabolism; D010320:Parvalbumins / Q000235:genetics*; D051381:Rats; D011914:Rats, Inbred BN; D011916:Rats, Inbred F344; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D014161:Transduction, Genetic / Q000379:methods; D016277:Ventricular Function, Left / Q000502:physiology*
D010320:Parvalbumins; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D000252:Calcium-Transporting ATPases