Abstract
The cardiac SERCA2 Ca2+ pump is critical for maintaining normal Ca2+ handling in the heart. Reduced SERCA2a content and blunted Ca2+ reuptake are frequently observed in failing hearts and evidence implicates poor cardiac Ca2+ 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 Ca2+ flux.
Highlights
Normal heart pump function requires the highly regulated, cyclical release and reuptake of Ca2+ in the myoplasm of cardiac myocytes
Defects in Ca2+ handling are clearly associated with cardiac dysfunction and heart failure[1,2,3,4,5,6]
Exons 2 and 3 of Serca2 gene locus are flanked by loxP sites, thereby allowing selective disruption of Serca2 in adult cardiac myocytes conferred by a tamoxifen-sensitive, cardiac myocyte-expressed MerCreMer transgene[12]
Summary
Normal heart pump function requires the highly regulated, cyclical release and reuptake of Ca2+ in the myoplasm of cardiac myocytes. Diminished Ca2+ flux and reduced SERCA2a expression are frequently observed in the failing heart, the exact relationship between these observations is not fully known. It is not clearly established whether loss of SERCA2a is a driving primary cause of severe cardiac dysfunction or whether this is a secondary consequence of the emerging cardiac pathology. A recently developed model of inducible SERCA2 knockout, the SERCA2 KO mouse, allows for selective disruption of the Serca gene in the hearts of adult mice[10,11] In this model, exons 2 and 3 of Serca gene locus are flanked by loxP sites, thereby allowing selective disruption of Serca in adult cardiac myocytes conferred by a tamoxifen-sensitive, cardiac myocyte-expressed MerCreMer transgene[12]
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