Fosinopril attenuates the doxorubicin-induced cardiomyopathy by restoring the function of sarcoplasmic reticulum.
Fosinopril, an angiotensin-converting enzyme inhibitor, is known to attenuate cardiomyopathy induced by doxorubicin (DOX); however, the mechanisms of this cardioprotection are not fully elucidated yet. In the present study, experimental cardiomyopathy was induced in rats by administration of DOX with or without co-treatment with fosinopril. Fosinopril was utilized on day 1 or 14 of the treatment with DOX to compare efficacies of early versus late co-treatments. We observed that fosinopril attenuated changes induced by DOX (e.g., less increased heart and left ventricular weights, diminished lung congestion and ascites, attenuated LVEDP and LVSP, and less decreased +dP/dt and -dP/dt). Further, fosinopril diminished the levels of markers of cardiac toxicity (i.e., plasma levels and activities of cardiac enzymes and proteins AST, LDH, CPK, cTnI, and BNP). Fosinopril also prevented DOX-induced decreases in Ca(2+) uptake and restored activity of Ca(2+)-stimulated ATPase in left ventricular sarcoplasmic reticulum. We next tested whether the improved Ca(2+) transport activity in sarcoplasmic reticulum was due to modulation of SERCA2 and phospholamban expressions by fosinopril. Fosinopril attenuated the decrease in SERCA2 and phospholamban expressions caused by DOX. In conclusion, cardioprotective effects of fosinopril in the DOX-induced cardiomyopathy appear to be due to its ability to prevent remodeling of the cardiac sarcoplasmic reticulum membrane.
Division of Cardiology, Xinhua Hospital School of Medicine, Shanghai Jiaotong University, 1665 Kong Jiang Road, Shanghai 200092, China.
Ya-chen
YC
Zhang
Yong
Y
Tang
Min
M
Zhang
Jian
J
Chen
Qing
Q
Zhou
Ying-gang
YG
Sun
Man-tian
MT
Chen
Wei-ping
WP
Xu
D000251:Adenosine Triphosphatases / Q000378:metabolism; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects; D001692:Biological Transport / Q000187:drug effects; D002118:Calcium / Q000378:metabolism; D002135:Calcium-Binding Proteins / Q000378:metabolism; D009202:Cardiomyopathies / Q000139:chemically induced* / Q000378:metabolism / Q000473:pathology* / Q000503:physiopathology; D004317:Doxorubicin / Q000009:adverse effects*; D004347:Drug Interactions; D017328:Fosinopril / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects; D006352:Heart Ventricles / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D006439:Hemodynamics / Q000187:drug effects; D008297:Male; D009206:Myocardium / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D020127:Recovery of Function / Q000187:drug effects*; D012519:Sarcoplasmic Reticulum / Q000187:drug effects* / Q000378:metabolism*; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000378:metabolism; D013997:Time Factors; D000099211:Phospholamban
D000251:Adenosine Triphosphatases; D000806:Angiotensin-Converting Enzyme Inhibitors; D000970:Antineoplastic Agents; D002118:Calcium; D002135:Calcium-Binding Proteins; D004317:Doxorubicin; D017328:Fosinopril; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D000099211:Phospholamban; C506948:Atp2a2 protein, rat