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...

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Bibliographic Details
Published in:PloS one 2013-11, Vol.8 (11), p.e79609-e79609
Main Authors: Heinis, Frazer I, Andersson, Kristin B, Christensen, Geir, Metzger, Joseph M
Format: Article
Language:English
Subjects:
Animals
Biology
Ca2+-transporting ATPase
Caffeine
Calcium
Calcium - metabolism
Calcium ions
Cardiomyocytes
Gene Knockout Techniques
Genotype & phenotype
Heart - physiology
Heart diseases
Heart failure
Heart function
Ischemia
Mechanical properties
Medical research
Mice
Models, Animal
Perfusion
Physiology
Proteins
Reperfusion
Rodents
Sarcoplasmic Reticulum - metabolism
Sarcoplasmic Reticulum Calcium-Transporting ATPases - deficiency
Sarcoplasmic Reticulum Calcium-Transporting ATPases - genetics
Sarcoplasmic Reticulum Calcium-Transporting ATPases - metabolism
Studies
Time Factors
Ventricular Function, Left
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Summary: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.
ISSN:1932-6203
1932-6203
DOI:10.1371/journal.pone.0079609