Antiplatelet therapy attenuates subcellular remodelling in congestive heart failure.
Antiplatelet agents, sarpogrelate (SAR), a 5-HT(2A) receptor antagonist, and cilostazol (CIL), a phosphodiesterase III (PDE-III) inhibitor, are used for the treatment of peripheral vascular disease. We tested whether these agents affect cardiac function and subcellular remodelling in congestive heart failure (CHF) induced by myocardial infarction (MI). Three weeks after MI, rats were treated daily with 5 mg/kg SAR or CIL as well as vehicle for 5 weeks. Sham-operated animals served as controls. At end of the treatment period, haemodynamic measurements were performed and the left ventricle was processed for the determination of sarcoplasmic reticulum (SR) Ca(2+)-uptake and -release activities, and expression of SR Ca(2+)-pump, phospholamban and ryanodine receptors, as well as myofibrillar ATPase activities, expression of alpha- and beta-myosin heavy chain (MHC) isoforms, and phosphorylation of phospholamban and cardiac troponin-I (c Tn-I). Marked haemodynamic changes in the MI-induced CHF were associated with depressions in SR Ca (+)-uptake and -release activities as well as in protein content and gene expression for SR proteins. Furthermore, myofibrillar Ca(2+)-stimulated ATPase activity, as well as protein content and gene expression for alpha-MHC were decreased whereas those for beta-MHC were increased in the failing heart. Also, phosphorylation levels of phospholamban and cTn-I were reduced in failing hearts. The MI-associated changes in cardiac function, SR and myofibillar activities, as well as SR and myofibrillar protein and gene expression were attenuated by treatment with SAR or CIL. The results suggest that SAR and CIL improve cardiac function by ameliorating subcellular remodelling in the failing heart and indicate the potential therapy of CHF with antiplatelet agents.
Sanganalmath
Santosh K
SK
Institute of Cardiovascular Sciences, St. Boniface General Hospital Research Center, Faculty of Medicine, University of Manitoba, Winnipeg, Canada.
Babick
Andrea P
AP
Barta
Judit
J
Kumamoto
Hideo
H
Takeda
Nobuakiya
N
Dhalla
Naranjan S
NS
D000251:Adenosine Triphosphatases / Q000378:metabolism; D000818:Animals; D001792:Blood Platelets; D002118:Calcium / Q000378:metabolism; D005786:Gene Expression Regulation; D006333:Heart Failure / Q000235:genetics / Q000378:metabolism / Q000601:surgery / Q000628:therapy*; D006439:Hemodynamics; D008297:Male; D018995:Myosin Heavy Chains / Q000378:metabolism; D020033:Protein Isoforms / Q000378:metabolism; D011506:Proteins / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D012519:Sarcoplasmic Reticulum / Q000378:metabolism; D013347:Subcellular Fractions / Q000378:metabolism
D020033:Protein Isoforms; D011506:Proteins; D012333:RNA, Messenger; D000251:Adenosine Triphosphatases; D018995:Myosin Heavy Chains; D002118:Calcium