Phospholemman deficiency in postinfarct hearts: enhanced contractility but increased mortality.
Phospholemman (PLM) regulates [Na(+) ](i), [Ca(2+)](i) and contractility through its interactions with Na(+)-K(+)-ATPase (NKA) and Na(+) /Ca(2+) exchanger (NCX1) in the heart. Both expression and phosphorylation of PLM are altered after myocardial infarction (MI) and heart failure. We tested the hypothesis that absence of PLM regulation of NKA and NCX1 in PLM-knockout (KO) mice is detrimental. Three weeks after MI, wild-type (WT) and PLM-KO hearts were similarly hypertrophied. PLM expression was lower but fractional phosphorylation was higher in WT-MI compared to WT-sham hearts. Left ventricular ejection fraction was severely depressed in WT-MI but significantly less depressed in PLM-KO-MI hearts despite similar infarct sizes. Compared with WT-sham myocytes, the abnormal [Ca(2+) ], transient and contraction amplitudes observed in WT-MI myocytes were ameliorated by genetic absence of PLM. In addition, NCX1 current was depressed in WT-MI but not in PLM-KO-MI myocytes. Despite improved myocardial and myocyte performance, PLM-KO mice demonstrated reduced survival after MI. Our findings indicate that alterations in PLM expression and phosphorylation are important adaptations post-MI, and that complete absence of PLM regulation of NKA and NCX1 is detrimental in post-MI animals.
Cardiovascular Division, Department of Medicine, University of Virginia Medical Center, Charlottesville, Virginia, USA.
M Ayoub
MA
Mirza
Susan
S
Lane
Zequan
Z
Yang
Themis
T
Karaoli
Kwame
K
Akosah
John
J
Hossack
Marcia
M
McDuffie
JuFang
J
Wang
Xue-Qian
XQ
Zhang
Jianliang
J
Song
Joseph Y
JY
Cheung
Amy L
AL
Tucker
D000818:Animals; D020013:Calcium Signaling; D048429:Cell Size; D006334:Heart Function Tests; D015640:Ion Channel Gating; D008565:Membrane Proteins / Q000172:deficiency* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008955:Models, Cardiovascular; D009200:Myocardial Contraction / Q000502:physiology*; D009203:Myocardial Infarction / Q000000981:diagnostic imaging / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology*; D009206:Myocardium / Q000378:metabolism* / Q000473:pathology*; D032383:Myocytes, Cardiac / Q000473:pathology; D009929:Organ Size; D010750:Phosphoproteins / Q000172:deficiency* / Q000378:metabolism; D010766:Phosphorylation; D000254:Sodium-Potassium-Exchanging ATPase / Q000378:metabolism; D016019:Survival Analysis; D014463:Ultrasonography
D008565:Membrane Proteins; D010750:Phosphoproteins; C069141:phospholemman; D000254:Sodium-Potassium-Exchanging ATPase