Abstract
OBJECTIVE: Vascular smooth muscle cell (VSMC) apoptosis is thought to contribute to atherosclerotic plaque instability. Cadherin mediates calcium-dependent homophilic cell-cell contact. We studied the role of N-cadherin in VSMC apoptosis.
METHODS AND RESULTS: Human saphenous vein VSMCs were grown in agarose-coated wells to allow cadherin-mediated aggregate formation. Cell death and apoptosis were determined after disruption of cadherins using several approaches (n> or =3 per approach). Calcium removal from culture medium or addition of nonspecific cadherin antagonist peptides significantly decreased aggregate formation and increased cell death by apoptosis (34+/-6% versus 75+/-1% and 19+/-1% versus 40+/-5%, respectively; P<0.05). Specific inhibition of N-cadherin using antagonists and neutralizing antibodies similarly increased apoptosis. Supporting this, overexpression of full-length N-cadherin significantly reduced VSMC apoptosis from 44+/-10% to 20+/-3% (P<0.05), whereas abolishing N-cadherin expression by overexpression of a dominant-negative N-cadherin significantly, even in the presence of cell-matrix contacts, increased apoptosis from 9+/-2% to 50+/-1% (P<0.05). Interestingly, cell-cell contacts provided a similar degree of protection from apoptosis to cell-matrix contacts. Finally, N-cadherin-mediated cell-cell contacts initiated anti-apoptotic signaling by increasing Akt and Bad phosphorylation.
CONCLUSIONS: Our results indicate that VSMC survival is dependent on N-cadherin-mediated cell-cell contacts, which could be important in the context of plaque instability.
Original language | English |
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Pages (from-to) | 982-8 |
Number of pages | 7 |
Journal | Arteriosclerosis, thrombosis, and vascular biology |
Volume | 25 |
Issue number | 5 |
DOIs | |
Publication status | Published - May 2005 |
Keywords
- Antibodies/pharmacology
- Apoptosis/physiology
- Atherosclerosis/metabolism
- Cadherins/genetics
- Calcium/metabolism
- Cell Aggregation/physiology
- Cell Communication/drug effects
- Cell Survival/physiology
- Cells, Cultured
- Extracellular Matrix/physiology
- Gene Expression
- Humans
- Muscle, Smooth, Vascular/cytology
- Saphenous Vein/cytology
- Signal Transduction/physiology