title: Targeted overexpression of the sarcoplasmic reticulum Ca2+-ATPase increases cardiac contractility in transgenic mouse hearts.
abstract: Cardiac hypertrophy and heart failure are known to be associated with a reduction in Ca2+-ATPase pump levels of the sarcoplasmic reticulum (SR). To determine whether, and to what extent, alterations in Ca2+ pump numbers can affect contraction and relaxation parameters of the heart, we have overexpressed the cardiac SR Ca2+-ATPase specifically in the mouse heart using the alpha-myosin heavy chain promoter. Analysis of 2 independent transgenic lines demonstrated that sarco(endo)plasmic reticulum Ca2+-ATPase isoform (SERCA2a) mRNA levels were increased 3.88+/-0. 4-fold and 7.90+/-0.2-fold over those of the control mice. SERCA2a protein levels were increased by 1.31+/-0.05-fold and 1.54+/-0. 05-fold in these lines despite high levels of mRNA, suggesting that complex regulatory mechanisms may determine the SERCA2a pump levels. The maximum velocity of Ca2+ uptake (Vmax) was increased by 37%, demonstrating that increased pump levels result in increased SR Ca2+ uptake function. However, the apparent affinity of the SR Ca2+-ATPase for Ca2+ remains unchanged in transgenic hearts. To evaluate the effects of overexpression of the SR Ca2+ pump on cardiac contractility, we used the isolated perfused work-performing heart model. The transgenic hearts showed significantly higher myocardial contractile function, as indicated by increased maximal rates of pressure development for contraction (+dP/dt) and relaxation (-dP/dt), together with shortening of the normalized time to peak pressure and time to half relaxation. Measurements of intracellular free calcium concentration and contractile force in trabeculae revealed a doubling of Ca2+ transient amplitude, with a concomitant boost in contractility. The present study demonstrates that increases in SERCA2a pump levels can directly enhance contractile function of the heart by increasing SR Ca2+ transport.
authors.affiliation: Division of Cardiology, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.
authors.forename: D L
authors.initials: DL
authors.lastname: Baker
authors.forename: K
authors.initials: K
authors.lastname: Hashimoto
authors.forename: I L
authors.initials: IL
authors.lastname: Grupp
authors.forename: Y
authors.initials: Y
authors.lastname: Ji
authors.forename: T
authors.initials: T
authors.lastname: Reed
authors.forename: E
authors.initials: E
authors.lastname: Loukianov
authors.forename: G
authors.initials: G
authors.lastname: Grupp
authors.forename: A
authors.initials: A
authors.lastname: Bhagwhat
authors.forename: B
authors.initials: B
authors.lastname: Hoit
authors.forename: R
authors.initials: R
authors.lastname: Walsh
authors.forename: E
authors.initials: E
authors.lastname: Marban
authors.forename: M
authors.initials: M
authors.lastname: Periasamy
mesh_terms: D000818:Animals; D001794:Blood Pressure; D002118:Calcium / Q000378:metabolism; D000252:Calcium-Transporting ATPases / Q000096:biosynthesis* / Q000235:genetics; D005260:Female; D006339:Heart Rate; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009200:Myocardial Contraction / Q000502:physiology*; D009206:Myocardium / Q000378:metabolism; D005082:Physical Exertion; D020033:Protein Isoforms / Q000096:biosynthesis / Q000235:genetics; D012333:RNA, Messenger / Q000096:biosynthesis; D012519:Sarcoplasmic Reticulum / Q000378:metabolism*; D019076:Transgenes / Q000502:physiology
chemical_list: D020033:Protein Isoforms; D012333:RNA, Messenger; D000252:Calcium-Transporting ATPases; D002118:Calcium