title: Hypoxia induces cardiac fibroblast proliferation and phenotypic switch: a role for caveolae and caveolin-1/PTEN mediated pathway.
abstract: BACKGROUND
  Cardiac fibrosis following myocardial infarction (MI) results in heart failure. Caveolin-1, the main structural protein of caveolae, regulates signal transduction pathways controlling cell proliferation and apoptosis. Meanwhile, low phosphatase and tensin homolog (PTEN) activity enhances the PI3K/Akt signal pathway to induce cell proliferation. But whether caveolin-1 and PTEN activation regulates cardiac fibroblast proliferation and contributes to cardiac fibrosis from ischemic injury is incompletely understood. This study investigates whether hypoxia inducing cardiac fibroblast proliferation and phenotypic switch is caveolin-dependent.
  
  
  METHODS
  We used in vitro and in vivo models of ischemic injury, immunohistochemical staining, and cell proliferation assays to address this hypothesis.
  
  
  RESULTS
  We found that MI induced collagen deposition and cardiac dysfunction. After MI, mice displayed reduced caveolin-1 and PTEN expression and increased α-smooth muscle actin (α-SMA) expression in the infarct zone. Qualitative and quantitative analyses indicated that caveolin-1 expression was lowest at 7 days after MI, accompanied by increased collagen deposition and attenuated cardiac function. We cultured cardiac fibroblasts of mice were in hypoxia or normoxia conditions for 12, 24 and 48 hours. At all the time points, caveolin-1 and PTEN expression were gradually reduced, whereas, α-SMA was gradually increased. We also observed that cell viability was increased at 12 and 24 h after hypoxia then lightly decreased at 48 h. Additionally, disruption of caveolae with methyl-β-cyclodextrin (MβCD) enhanced p-Akt and α-SMA expression and fibroblast proliferation and phenotypic switch.
  
  
  CONCLUSIONS
  These findings suggest a key role for caveolae, perhaps through the caveolin-1/PTEN signaling pathway, in cardiac fibroblast proliferation and phenotypic switch under hypoxia.
authors.affiliation: Department of Geriatrics, First Affiliated Hospital with Nanjing Medical University, Nanjing 210029, China.
authors.forename: Yao
authors.initials: Y
authors.lastname: Gao
authors.affiliation: Department of Geriatrics, First Affiliated Hospital with Nanjing Medical University, Nanjing 210029, China.
authors.forename: Ming
authors.initials: M
authors.lastname: Chu
authors.affiliation: Department of Geriatrics, First Affiliated Hospital with Nanjing Medical University, Nanjing 210029, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Hong
authors.affiliation: Department of Geriatrics, First Affiliated Hospital with Nanjing Medical University, Nanjing 210029, China.
authors.forename: Jingping
authors.initials: J
authors.lastname: Shang
authors.affiliation: Department of Geriatrics, First Affiliated Hospital with Nanjing Medical University, Nanjing 210029, China.
authors.forename: Di
authors.initials: D
authors.lastname: Xu
keywords: Caveolin-1; cardiac fibroblast; hypoxia; phosphatase and tensin homolog (PTEN)