title: Control by circulating factors of mitochondrial function and transcription cascade in heart failure: a role for endothelin-1 and angiotensin II.
abstract: BACKGROUND
  Evidence is emerging to support the concept that the failing heart is "energy depleted" and that defects in energy metabolism are important determinants in the development and the progression of the disease. We have shown previously that depressed mitochondrial function in cardiac and skeletal muscles in chronic heart failure is linked to decreased expression of the gene encoding transcriptional proliferator-activated receptor-gamma coactivator-1alpha, the inducible regulator of mitochondrial biogenesis and its transcription cascade, leading to altered expression of mitochondrial proteins. However, oxidative capacity of the myocardium of patients treated for chronic heart failure and pathophysiological mechanisms of mitochondrial dysfunction are still largely unknown.
  
  
  RESULTS
  In patients with chronic heart failure treated with angiotensin-converting enzyme inhibition, cardiac oxidative capacity, measured in saponin-permeabilized fibers, was 25% lower, and proliferator-activated receptor-gamma coactivator-1alpha protein content was 34% lower compared with nonfailing controls. In a rat model of myocardial infarction, angiotensin-converting enzyme inhibition therapy was only partially able to protect cardiac mitochondrial function and transcription cascade. Expression of proliferator-activated receptor-gamma coactivator-1alpha and its transcription cascade were evaluated after a 48-hour exposure of cultured adult rat ventricular myocytes to endothelin-1, angiotensin II, aldosterone, phenylephrine, or isoprenaline. Endothelin-1 (-30%) and, to a lesser degree, angiotensin II (-20%) decreased proliferator-activated receptor-gamma coactivator-1alpha mRNA content, whereas other hormones had no effect (phenylephrine) or even increased it (aldosterone, isoprenaline).
  
  
  CONCLUSIONS
  Taken together, these results show that, despite angiotensin-converting enzyme inhibition treatment, oxidative capacity is reduced in human and experimental heart failure and that endothelin-1 and angiotensin II could be involved in the downregulation of the mitochondrial transcription cascade.
authors.affiliation: INSERM, U-769, Châtenay-Malabry, France. anne.garnier@u-psud.fr
authors.forename: Anne
authors.initials: A
authors.lastname: Garnier
authors.forename: Joffrey
authors.initials: J
authors.lastname: Zoll
authors.forename: Dominique
authors.initials: D
authors.lastname: Fortin
authors.forename: Benoît
authors.initials: B
authors.lastname: N'Guessan
authors.forename: Florence
authors.initials: F
authors.lastname: Lefebvre
authors.forename: Bernard
authors.initials: B
authors.lastname: Geny
authors.forename: Bertrand
authors.initials: B
authors.lastname: Mettauer
authors.forename: Vladimir
authors.initials: V
authors.lastname: Veksler
authors.forename: Renée
authors.initials: R
authors.lastname: Ventura-Clapier
mesh_terms: D000804:Angiotensin II / Q000097:blood*; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000627:therapeutic use; D000818:Animals; D015536:Down-Regulation; D019332:Endothelin-1 / Q000097:blood*; D005260:Female; D006333:Heart Failure / Q000097:blood* / Q000188:drug therapy / Q000503:physiopathology*; D006360:Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D008297:Male; D008875:Middle Aged; D008929:Mitochondria, Heart / Q000378:metabolism*; D010101:Oxygen Consumption; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D051381:Rats; D014157:Transcription Factors / Q000378:metabolism
chemical_list: D000806:Angiotensin-Converting Enzyme Inhibitors; D019332:Endothelin-1; D006360:Heat-Shock Proteins; C486497:PPARGC1A protein, human; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D014157:Transcription Factors; D000804:Angiotensin II