title: Sarcoplasmic reticulum function and carnitine palmitoyltransferase-1 inhibition during progression of heart failure.
abstract: Failing cardiac hypertrophy is associated with an inadequate sarcoplasmic reticulum (SR) function. The hypothesis was examined that pressure overloaded hearts fail to increase SR Ca(2+) uptake rate proportionally to the hypertrophy and that carnitine palmitoyltransferase-1 inhibition by etomoxir ((+/-)-ethyl 2[6(4-chlorophenoxy)hexyl] oxirane-2-carboxylate) can counteract this process. Severe left ventricular pressure overload was induced in rats by constricting the ascending aorta for 8, 10, 14 and 28 weeks leading to cardiac hypertrophy (+62 - +103% of sham-operated rats) and pulmonary congestion. Homogenate oxalate-facilitated SR Ca(2+) uptake rate g wet wt(-1) was reduced (P<0.05) by 29.9+/-1.8% irrespective of phospholamban phosphorylation (in the presence of catalytic subunit of protein kinase A) and inhibition of SR Ca(2+) release channel by ruthenium red. SERCA2 protein level was reduced (P<0.05) by 30.4+/-0.8%. SR Ca(2+) uptake rate was inversely correlated (P<0.05) with left ventricular weight but was not affected by the occurrence of pulmonary congestion. Because SR Ca(2+) uptake rate of whole ventricles was not reduced, a hypertrophy proportional dilution of SR Ca(2+) uptake has to be inferred which precedes pulmonary congestion. Treatment with etomoxir (15 mg kg body wt(-1) day(-1) for 10 weeks) did not affect left ventricular weight but decreased (P:<0.05) the right ventricular hypertrophy related to pulmonary congestion. In parallel, SR Ca(2+) uptake rate of left ventricle and myosin isozyme V(1) were increased (P<0.05). Etomoxir represents a candidate approach for prevention of heart failure by inducing a hypertrophy proportional increase in SR Ca(2+) uptake rate.
authors.affiliation: Molecular Cardiology Laboratory, Department of Internal Medicine and Cardiology, Philipps University of Marburg, 35033 Marburg, Germany. Rupp@mailer.uni-marburg.de
authors.forename: H
authors.initials: H
authors.lastname: Rupp
authors.forename: R
authors.initials: R
authors.lastname: Vetter
mesh_terms: D000818:Animals; D001024:Aortic Valve Stenosis / Q000503:physiopathology; D001835:Body Weight; D002118:Calcium / Q000493:pharmacokinetics; D000252:Calcium-Transporting ATPases / Q000378:metabolism; D002334:Carnitine O-Palmitoyltransferase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D018450:Disease Progression; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004852:Epoxy Compounds / Q000494:pharmacology; D006333:Heart Failure / Q000378:metabolism / Q000473:pathology* / Q000517:prevention & control; D006352:Heart Ventricles / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D006984:Hypertrophy / Q000517:prevention & control; D007527:Isoenzymes / Q000187:drug effects / Q000378:metabolism; D009218:Myosins / Q000187:drug effects / Q000378:metabolism; D009929:Organ Size; D051381:Rats; D017208:Rats, Wistar; D012519:Sarcoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D013997:Time Factors
chemical_list: C506948:Atp2a2 protein, rat; D004791:Enzyme Inhibitors; D004852:Epoxy Compounds; D007527:Isoenzymes; D002334:Carnitine O-Palmitoyltransferase; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D009218:Myosins; D000252:Calcium-Transporting ATPases; C054207:etomoxir; D002118:Calcium