Effect of angiotensin-converting enzyme inhibition on protein kinase C and SR proteins in heart failure.
We tested the hypothesis that activation of protein kinase C (PKC) isoforms in pressure-overload heart failure was prevented by angiotensin-converting enzyme (ACE) inhibition, resulting in normalization of cardiac sarcoplasmic reticulum (SR) Ca2+ ATPase (SERCA) 2a and phospholamban protein levels and improvement in intracellular Ca2+ handling. Aortic-banded and control guinea pigs were given ramipril (5 mg. kg-1. day-1) or placebo for 8 wk. Ramipril-treated banded animals had lower left ventricular (LV) and lung weight, improved survival, increased isovolumic LV mechanics, and improved cardiomyocyte Ca2+ transients compared with placebo-treated banded animals. This was associated with maintenance of SERCA2a and phospholamban protein expression. Translocation of PKC-alpha and -epsilon was increased in placebo-treated banded guinea pigs compared with controls and was attenuated significantly by treatment with ramipril. We conclude that ACE inhibition attenuates PKC translocation and prevents downregulation of Ca2+ cycling protein expression in pressure-overload hypertrophy. This represents a mechanism for the beneficial effects of this therapy on LV function and survival in heart failure.
Takeishi
Y
Y
Division of Cardiology, University of Cincinnati College of Medicine, Cincinnati, Ohio 45267, USA.
Bhagwat
A
A
Ball
N A
NA
Kirkpatrick
D L
DL
Periasamy
M
M
Walsh
R A
RA
D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D001826:Body Fluids / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D002135:Calcium-Binding Proteins / Q000378:metabolism; D000252:Calcium-Transporting ATPases / Q000378:metabolism; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects / Q000503:physiopathology; D006333:Heart Failure / Q000378:metabolism* / Q000503:physiopathology; D017379:Hypertrophy, Left Ventricular / Q000473:pathology; D008168:Lung / Q000187:drug effects / Q000378:metabolism; D008297:Male; D009124:Muscle Proteins / Q000378:metabolism*; D009206:Myocardium / Q000473:pathology; D011493:Protein Kinase C / Q000378:metabolism*; D017257:Ramipril / Q000494:pharmacology*; D012519:Sarcoplasmic Reticulum / Q000201:enzymology / Q000378:metabolism*; D016019:Survival Analysis; D000099211:Phospholamban
D000806:Angiotensin-Converting Enzyme Inhibitors; D002118:Calcium; D002135:Calcium-Binding Proteins; D000252:Calcium-Transporting ATPases; D009124:Muscle Proteins; D011493:Protein Kinase C; D017257:Ramipril; D000099211:Phospholamban