Parvalbumin gene transfer corrects diastolic dysfunction in diseased cardiac myocytes.
Heart failure frequently involves diastolic dysfunction that is characterized by a prolonged relaxation. This prolonged relaxation is typically the result of a decreased rate of intracellular Ca(2+) sequestration. No effective treatment for this decreased Ca(2+) sequestration rate currently exists. As an approach to possibly correct diastolic dysfunction, we hypothesized that expression of the Ca(2+) binding protein parvalbumin in cardiac myocytes would lead to increased rates of Ca(2+) sequestration and mechanical relaxation. Parvalbumin, which is normally absent in cardiac tissue, is known to act as a soluble relaxing factor in fast skeletal muscle fibers by acting as a delayed Ca(2+) sink. As a test of the hypothesis, gene transfer was used to express parvalbumin in isolated adult cardiac myocytes. We report here that expression of parvalbumin dramatically increases the rate of Ca(2+) sequestration and the relaxation rate in normal cardiac myocytes. Importantly, parvalbumin fully restored the relaxation rate in diseased cardiac myocytes isolated from an animal model of human diastolic dysfunction. These findings indicate that parvalbumin gene transfer offers unique potential as a possible direct treatment for diastolic dysfunction in failing hearts.
Wahr
P A
PA
Department of Physiology, University of Michigan, Ann Arbor, MI 48109, USA. pwahr@umich.edu
Michele
D E
DE
Metzger
J M
JM
D000818:Animals; D015153:Blotting, Western; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D003971:Diastole / Q000235:genetics*; D004195:Disease Models, Animal; D005260:Female; D018014:Gene Transfer Techniques; D006333:Heart Failure / Q000235:genetics* / Q000628:therapy*; D007037:Hypothyroidism / Q000378:metabolism / Q000628:therapy; D009206:Myocardium / Q000378:metabolism; D010320:Parvalbumins / Q000235:genetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012518:Sarcomeres / Q000378:metabolism; D013997:Time Factors
D010320:Parvalbumins; D002118:Calcium