Ablation of phospholamban and sarcolipin results in cardiac hypertrophy and decreased cardiac contractility.
OBJECTIVE
Improving the sarco(endo)plasmic reticulum (SR) Ca(2+)-ATPase (SERCA) function has clinical implications in treating heart failure. The present study aimed to determine the effect of constitutive activation of the SERCA pump on cardiac contractility in normal mice and during pressure-overload-induced cardiac hypertrophy.


RESULTS
The SERCA pump was constitutively activated in both atrial and ventricular chambers of the mouse heart by ablating its key regulators, phospholamban (PLN) and sarcolipin (SLN). The double-knockout (dKO) mice for PLN and SLN showed increased SERCA pump activity, Ca(2+) transients and SR Ca(2+) load, and developed cardiac hypertrophy. Echocardiographic measurements showed that the basal cardiac function was not affected in the young dKO mice. However, the cardiac function worsened upon ageing and when subjected to pressure overload.


CONCLUSIONS
Our studies suggest that the constitutive activation of the SERCA pump is detrimental to cardiac function. Our findings also emphasize the need for dynamic regulation of the SERCA pump by PLN and/or SLN to maintain cardiac contractility in normal conditions and during pathophysiological states.
Shanmugam
Mayilvahanan
M
Department of Cell Biology and Molecular Medicine, University of Medicine and Dentistry of New Jersey-New Jersey Medical School, 185 South Orange Avenue, MSB, G609, Newark, NJ 07103, USA.
Gao
Shumin
S
Hong
Chull
C
Fefelova
Nadezhda
N
Nowycky
Martha C
MC
Xie
Lai-Hua
LH
Periasamy
Muthu
M
Babu
Gopal J
GJ
D000367:Age Factors; D000375:Aging; D000818:Animals; D001011:Aorta / Q000601:surgery; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling; D002135:Calcium-Binding Proteins / Q000172:deficiency* / Q000235:genetics; D006332:Cardiomegaly / Q000000981:diagnostic imaging / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D004195:Disease Models, Animal; D004789:Enzyme Activation; D005260:Female; D005786:Gene Expression Regulation; D008026:Ligation; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009124:Muscle Proteins / Q000172:deficiency* / Q000235:genetics; D009200:Myocardial Contraction / Q000235:genetics; D009206:Myocardium / Q000378:metabolism*; D011510:Proteolipids / Q000172:deficiency* / Q000235:genetics; D012519:Sarcoplasmic Reticulum / Q000378:metabolism; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000378:metabolism; D013318:Stroke Volume; D014463:Ultrasonography; D016277:Ventricular Function, Left; D000099211:Phospholamban
D002118:Calcium; D002135:Calcium-Binding Proteins; D009124:Muscle Proteins; D011510:Proteolipids; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D000099211:Phospholamban; C077258:sarcolipin