Abstract 15676: Chronic Activation of Platelet-derived Growth Factor βReceptor Signaling in Vascular Smooth Muscle Cells Increases Apoptosis in Atherosclerotic Plaques via Downregulation of Bcl-2
Apoptosis of vascular smooth muscle cells (VSMC) promotes instability of atherosclerotic plaques thereby contributing to plaque rupture and myocardial infarction. Receptor tyrosine kinases like the platelet-derived growth factor beta receptor (PDGFR), are believed to protect against apoptosis via PI 3-kinase (PI3K) dependent signaling pathways. Here, we investigated the effects of chronically elevated PDGFR/PI3K signaling in VSMCs on apoptosis in atherosclerotic plaques. To this end, we quantified TUNEL (TdT-mediated dUTP-biotin nick end labeling)-positive VSMCs in lesions from 12 to 15 months old LDLR-/-/smLRP1-/- double knockout mice. Whereas LDLR (low-density lipoprotein receptor) deficiency serves as an atherosclerosis mouse model, VSMC specific LRP1 (low-density lipoprotein receptor-related protein 1) knockout causes elevated PDGFR expression and signaling in VSMCs. LDLR-/-/smLRP1-/- increased the percentage of TUNEL-positive cells compared to LDLR-/-/smLRP1+/+ controls (3,6%±0,7% versus 0.7% ± 0.3%,respectively, P < 0.05, n = 6 mice, respectively). Furthermore, mutation of the PI3K binding site in the PDGFR polypeptide (F2-mutation) in LDLR-/-/smLRP1-/--F2/F2 mice suppressed VSMC apoptosis in plaques (2,4%±0,3% versus 3.6%±0.7%, P < 0.05, n = 6, respectively). These data suggest that the PDGFR exerts proapoptotic effects via PI3K. Further immunohistochemical analysis of atherosclerotic plaques from LDLR-/-/smLRP1-/- and LDLR-/-/smLRP1-/--F2/F2 mice revealed that PDGFR dependent activation of PI3K impairs the expression of antiapoptotic Bcl-2. In vivo, PDGF dependent downregulation of Bcl-2 increased the susceptibility of cultured VSMCs to apoptotic agonists like H2O2 or Fas ligand. Finally, we found that PDGF mediated downregulation of Bcl-2 involves the PI3K dependent induction of c-Myc. In conclusion, our study identified a new PDGFR dependent proapoptotic signaling pathway. Chronically elevated PDGFR signaling in VSMCs downregulates Bcl-2 via PI3K dependent induction of c-Myc. This has direct implications in atherogenesis, as PDGF promotes cell death in atherosclerotic plaques which can ultimately lead to plaque instability and rupture.
- © 2011 by American Heart Association, Inc.