Prominent heart organ-level performance deficits in a genetic model of targeted severe and progressive SERCA2 deficiency.
The cardiac SERCA2 Ca(2+) pump is critical for maintaining normal Ca(2+) handling in the heart. Reduced SERCA2a content and blunted Ca(2+) reuptake are frequently observed in failing hearts and evidence implicates poor cardiac Ca(2+) handling in the progression of heart failure. To gain insight into mechanism we investigated a novel genetic mouse model of inducible severe and progressive SERCA2 deficiency (inducible Serca2 knockout, SERCA2 KO). These mice eventually die from overt heart failure 7-10 weeks after knockout but as yet there have been no reports on intrinsic mechanical performance at the isolated whole heart organ level. Thus we studied whole-organ ex vivo function of hearts isolated from SERCA2 KO mice at one and four weeks post-knockout in adult animals. We found that isolated KO heart function was only modestly impaired one week post-knockout, when SERCA2a protein was 32% of normal. At four weeks post-knockout, function was severely impaired with near non-detectable levels of SERCA2. During perfusion with 10 mM caffeine, LV developed pressures were similar between 4-week KO and control hearts, and end-diastolic pressures were lower in KO. When hearts were subjected to ischemia-reperfusion injury, recovery was not different between control and KO hearts at either one or four weeks post-knockout. Our findings indicate that ex vivo function of isolated SERCA2 KO hearts is severely impaired long before symptoms appear in vivo, suggesting that physiologically relevant heart function in vivo can be sustained for weeks in the absence of robust SR Ca(2+) flux.
Department of Integrative Biology and Physiology, University of Minnesota Medical School, Minneapolis, Minnesota, United States of America ; Department of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota, Minneapolis, Minnesota, United States of America.
Frazer I
FI
Heinis
Kristin B
KB
Andersson
Geir
G
Christensen
Joseph M
JM
Metzger
D000818:Animals; D002118:Calcium / Q000378:metabolism; D055786:Gene Knockout Techniques; D006321:Heart / Q000502:physiology*; D051379:Mice; D023421:Models, Animal; D012519:Sarcoplasmic Reticulum / Q000378:metabolism*; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D013997:Time Factors; D016277:Ventricular Function, Left
D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D002118:Calcium