Role of SR Ca2+-ATPase in contractile dysfunction of myocytes in tachycardia-induced heart failure.
Sarcoplasmic reticulum (SR) Ca2+-ATPase gene expression is reduced in the failing myocardium. However, the functional relevance of these changes to myocardial contractility is not yet established. We assessed myocardial contractile function by analyzing sarcomere motion of isolated myocytes and also quantified SR Ca2+ regulatory protein gene expression by Northern blot analysis in the same hearts obtained from 10 dogs with pacing-induced heart failure (HF; 240 beats/min, 4 wk) and 7 control dogs. Sarcomere-shortening velocity was depressed in HF myocytes, accompanied by the prolongation of intracellular Ca2+ concentration ([Ca2+]i) transient measured by indo 1 fluorescence ratio. SR Ca2+-ATPase mRNA levels (normalized to glyceraldehyde-3-phosphate dehydrogenase mRNA) were significantly depressed in HF, and calsequestrin mRNA was increased. For control and HF dogs, sarcomere-shortening velocity correlated positively with Ca2+-ATPase mRNA levels (r = 0.73, n = 17, P < 0.01) but not with calsequestrin mRNA. Ca2+-ATPase mRNA levels were correlated with 45Ca2+ uptake rate by SR, which was also reduced in HF. Moreover, the inhibition of SR Ca2+-ATPase with thapsigargin or cyclopiazonic acid reproduced in normal myocytes the abnormalities observed in HF myocytes, such as depressed contractility and the prolonged [Ca2+]i transient duration. A downregulation of Ca2+-ATPase gene expression and a resultant decrease in Ca2+ uptake by SR may be responsible for the contractile dysfunction and the alterations of [Ca2+]i transient in HF.
Research Institute of Angiocardiology and Cardiovascular Clinic, Kyushu University School of Medicine, Fukuoka 812-82, Japan.
K
K
Igarashi-Saito
H
H
Tsutsui
S
S
Yamamoto
M
M
Takahashi
S
S
Kinugawa
H
H
Tagawa
M
M
Usui
M
M
Yamamoto
K
K
Egashira
A
A
Takeshita
D000818:Animals; D002118:Calcium / Q000378:metabolism; D000252:Calcium-Transporting ATPases / Q000096:biosynthesis*; D002155:Calsequestrin / Q000096:biosynthesis; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004285:Dogs; D004452:Echocardiography; D006321:Heart / Q000187:drug effects / Q000502:physiology / Q000503:physiopathology*; D006333:Heart Failure / Q000209:etiology / Q000503:physiopathology*; D009200:Myocardial Contraction; D009206:Myocardium / Q000201:enzymology*; D012333:RNA, Messenger / Q000096:biosynthesis; D012518:Sarcomeres / Q000187:drug effects / Q000502:physiology; D012519:Sarcoplasmic Reticulum / Q000201:enzymology*; D013610:Tachycardia / Q000150:complications / Q000503:physiopathology*; D019284:Thapsigargin / Q000494:pharmacology; D013997:Time Factors; D014158:Transcription, Genetic; D016277:Ventricular Function, Left / Q000502:physiology*
D002155:Calsequestrin; D012333:RNA, Messenger; D019284:Thapsigargin; D000252:Calcium-Transporting ATPases; D002118:Calcium