The fall in creatine levels and creatine kinase isozyme changes in the failing heart are reversible: complex post-transcriptional regulation of the components of the CK system.
Decreases in total creatine kinase (CK) activity and creatine [Cr] combine to limit the capacity of the failing heart to rapidly re-synthesize ATP (energy reserve). If the loss in energy reserve could be reversed, cardiac contractile reserve may be improved. Here we test whether these changes are reversible during recovery from heart failure. Left ventricular (LV) contractile function was measured in chronically instrumented conscious dogs with heart failure (CHF) induced by cardiac pacing for 3-4 weeks, and after recovery from heart failure (Recovery) (unpaced) for 5-6 weeks. LV contractile function and contractile reserve were depressed in CHF but returned to control in Recovery. CK capacity fell by 55% in CHF due to decreases in [Cr] (-39%) and CK activity (-25%), but was fully restored in Recovery. CK-B isozyme activity, protein (Western) and mRNA levels (real time PCR), respectively, were higher by 2-, 5.4- and 11-fold in CHF and higher by 3-, 2- and 2-fold in Recovery. CK-MM activity was decreased (-30%) in CHF but returned to normal levels during Recovery; CK-M protein was 30% lower in both CHF and Recovery even though there were no changes in mRNA levels. A similar pattern was found for mitochondrial CK (sMtCK). Deceases in CK activity and [Cr] in CHF are reversible. Decreases in CK-MM and sMtCK activities, but not the increases in CK-BB and CK-MB, also reversed. Neither the changes in protein nor mRNA levels for CK-B and CK-M correlated to their activities, suggesting that CK is under complex post-transcriptional regulation.
Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285, USA. shen_weiqun@lilly.com
Weiqun
W
Shen
Matthias
M
Spindler
Marnie A
MA
Higgins
Najia
N
Jin
Robert M
RM
Gill
Laura J
LJ
Bloem
Timothy P
TP
Ryan
Joanne S
JS
Ingwall
D000818:Animals; D015153:Blotting, Western; D002304:Cardiac Pacing, Artificial; D002316:Cardiotonic Agents / Q000494:pharmacology; D003401:Creatine / Q000032:analysis* / Q000378:metabolism; D003402:Creatine Kinase / Q000032:analysis* / Q000235:genetics / Q000378:metabolism; D052276:Creatine Kinase, BB Form; D052283:Creatine Kinase, MM Form; D004280:Dobutamine / Q000494:pharmacology; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases / Q000032:analysis / Q000378:metabolism; D006333:Heart Failure / Q000201:enzymology* / Q000209:etiology / Q000378:metabolism*; D007527:Isoenzymes / Q000032:analysis / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000032:analysis / Q000378:metabolism; D011897:Random Allocation; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors
D002316:Cardiotonic Agents; D007527:Isoenzymes; D012333:RNA, Messenger; D004280:Dobutamine; D005987:Glyceraldehyde-3-Phosphate Dehydrogenases; D003402:Creatine Kinase; D052276:Creatine Kinase, BB Form; D052283:Creatine Kinase, MM Form; D003401:Creatine