title: Mechanical unloading increases caveolin expression in the failing human heart.
abstract: OBJECTIVE
  Implantation of a left ventricular assist device (LVAD) in the failing human heart initiates structural and functional changes termed reverse remodeling. Mechanical unloading improves cardiac adrenergic responsiveness and lipid metabolism, processes regulated by caveolar function. We tested the hypothesis that mechanical unloading alters the expression of caveolins and these changes are linked to altered expression of markers of reverse remodeling.
  
  
  METHODS
  Paired human myocardial samples were obtained from patients who received an LVAD as a bridge to cardiac transplantation. Transcript levels were measured using real-time Q-RT-PCR in RNA prepared from 34 pairs of formalin-fixed myocardial tissue blocks. Caveolin-1 and -3 protein levels were determined from frozen tissue (n=5) by Western blots. Caveolin-3 localization was demonstrated by immunohistochemistry.
  
  
  RESULTS
  Caveolin-1 protein levels were upregulated in all LVAD-patients after mechanical unloading (P=0.002). Caveolin-1 mRNA was increased in 76% of the patients (n=34, P<0.001). Larger induction of caveolin-1 was associated with greater suppression of ANF. Caveolin-3 transcript levels increased in 82% of the cohort, along with a 2.5-fold induction of caveolin-2. Sarcolemmal caveolin-3 staining was increased after LVAD-support, although no change in total caveolin-3 protein was detected. The mRNA levels of the caveolin-associated CD36 also increased with unloading. Patients with ischemic cardiomyopathy showed greater induction of CD36 (P<0.05) than non-ischemic cases, as well as highly correlated changes in the expression of caveolin isoforms.
  
  
  CONCLUSIONS
  Mechanical unloading induces the expression of caveolins and CD36. The induction of caveolin-1 and the reciprocal suppression of ANF suggest that the changes in the expression of both genes are linked to decreased hemodynamic load. Enhanced caveolin expression during mechanical unloading of failing human hearts may be a part of the reverse remodeling of lipid metabolism, nitric oxide production and adrenergic signaling.
authors.affiliation: Department of Integrative Biology and Pharmacology, University of Texas at Houston Medical School, P.O. Box 20708, Houston, TX 77225, USA.
authors.forename: Iván P
authors.initials: IP
authors.lastname: Uray
authors.forename: John H
authors.initials: JH
authors.lastname: Connelly
authors.forename: O Howard
authors.initials: OH
authors.lastname: Frazier
authors.forename: Heinrich
authors.initials: H
authors.lastname: Taegtmeyer
authors.forename: Peter J A
authors.initials: PJ
authors.lastname: Davies
mesh_terms: D000328:Adult; D009320:Atrial Natriuretic Factor / Q000032:analysis / Q000378:metabolism; D015153:Blotting, Western / Q000379:methods; D018955:CD36 Antigens / Q000032:analysis / Q000235:genetics; D051242:Caveolin 1; D051243:Caveolin 2; D051244:Caveolin 3; D022461:Caveolins / Q000032:analysis / Q000235:genetics*; D016000:Cluster Analysis; D006333:Heart Failure / Q000378:metabolism / Q000628:therapy*; D006353:Heart-Assist Devices; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D008875:Middle Aged; D017202:Myocardial Ischemia / Q000378:metabolism / Q000628:therapy; D009206:Myocardium / Q000737:chemistry / Q000378:metabolism*; D012333:RNA, Messenger / Q000032:analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: C495540:CAV1 protein, human; D018955:CD36 Antigens; D051242:Caveolin 1; D051243:Caveolin 2; D051244:Caveolin 3; D022461:Caveolins; D012333:RNA, Messenger; D009320:Atrial Natriuretic Factor