title: The use of partial fatty acid oxidation inhibitors for metabolic therapy of angina pectoris and heart failure.
abstract: Partial fatty acid oxidation inhibitors have raised great interest since they are expected to counteract a dysregulated gene expression of hypertrophied cardiocytes. Some of these compounds have been developed for treating non-insulin-dependent diabetes mellitus and stable angina pectoris. A shift from fatty acid oxidation to glucose oxidation leads to a reduced gluconeogenesis and improved economy of cardiac work. An increased glucose oxidation can be achieved with the following enzyme inhibitors: etomoxir, oxfenicine, methyl palmoxirate, S-15176, metoprolol, amiodarone, perhexiline (carnitine palmitoyltransferase-1); aminocarnitine, perhexiline (carnitine palmitoyltransferase-2); hydrazonopropionic acid (carnitine-acylcarnitine translocase); MET-88 (gamma-butyrobetaine hydroxylase); 4-bromocrotonic acid, trimetazidine, possibly ranolazine (thiolases); hypoglycin (butyryl-CoA dehydrogenase); dichloroacetate (pyruvate dehydrogenase kinase). CLINICAL TRIALS with trimetazidine and ranolazine showed that this shift in substrate oxidation has an antianginal action. Etomoxir and MET-88 improved the function of overloaded hearts by increasing the density of the Ca(2+) pump of sarcoplasmic reticulum (SERCA2). The promoters of SERCA2 and alpha-myosin heavy-chain exhibit sequences which are expected to respond to transcription factors responsive to glucose metabolites and/or peroxisome proliferator-responsive element (PPAR) agonists. Further progress in elucidating novel compounds which upregulate SERCA2 expression is closely linked to the characterization of regulatory sequences of the SERCA2 promoter.
authors.affiliation: Molecular Cardiology Laboratory, Department of Internal Medicine and Cardiology, University of Marburg, Germany. Rupp@mailer.uni-marburg.de
authors.forename: Heinz
authors.initials: H
authors.lastname: Rupp
authors.forename: Angel
authors.initials: A
authors.lastname: Zarain-Herzberg
authors.forename: Bernhard
authors.initials: B
authors.lastname: Maisch
mesh_terms: D000083:Acetanilides; D000787:Angina Pectoris / Q000188:drug therapy* / Q000378:metabolism*; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002317:Cardiovascular Agents / Q000627:therapeutic use*; D002986:Clinical Trials as Topic; D004791:Enzyme Inhibitors / Q000627:therapeutic use*; D004852:Epoxy Compounds / Q000627:therapeutic use*; D005227:Fatty Acids / Q000378:metabolism*; D015870:Gene Expression; D005947:Glucose / Q000378:metabolism; D006333:Heart Failure / Q000188:drug therapy* / Q000378:metabolism*; D006801:Humans; D007004:Hypoglycemic Agents / Q000627:therapeutic use*; D008763:Methylhydrazines / Q000627:therapeutic use*; D032383:Myocytes, Cardiac / Q000378:metabolism; D010084:Oxidation-Reduction; D010879:Piperazines / Q000627:therapeutic use*; D000069458:Ranolazine; D051381:Rats; D017208:Rats, Wistar; D012519:Sarcoplasmic Reticulum / Q000378:metabolism; D014292:Trimetazidine / Q000627:therapeutic use*; D015854:Up-Regulation; D014665:Vasodilator Agents / Q000627:therapeutic use*
chemical_list: D000083:Acetanilides; D002317:Cardiovascular Agents; D004791:Enzyme Inhibitors; D004852:Epoxy Compounds; D005227:Fatty Acids; D007004:Hypoglycemic Agents; D008763:Methylhydrazines; D010879:Piperazines; D014665:Vasodilator Agents; C050147:3-(2,2,2-trimethylhydrazine)propionate; D000069458:Ranolazine; D005947:Glucose; C054207:etomoxir; D014292:Trimetazidine; D002118:Calcium