HRT1 modulates vascular smooth muscle cell proliferation and apoptosis.
The Notch signaling pathway plays vital roles in vascular development and homeostasis. However, the functional role of HRT1, a primary downstream effector of Notch signaling in VSMC, is poorly characterized. In the present study, we postulated that HRT1 plays fundamental roles in modulating VSMC fate. To test the hypothesis that HRT1 is coupled to growth regulation, we generated VSMC lines constitutively overexpressing HRT1 (HRT1SMC) and demonstrated an exaggerated growth behavior compared to its control cell line. The lack of cell cycle arrest at confluence in HRT1SMC was associated with an attenuated up-regulation of the cell cycle inhibitor, p21(WAF1/CIP1). We further established that both transient and constitutive HRT1 signaling promoted VSMC survival in response to serum deprivation and pro-apoptotic Fas ligand. Resistance to apoptosis was associated with the induction of Akt expression/activity, a well-described anti-apoptotic mediator. Overall, these findings provide initial evidence that HRT1 functions as a critical determinant of VSMC proliferation and survival.
Wang
Wenli
W
Cardiovascular Research Institute, Morehouse School of Medicine, Atlanta, GA 30310, USA. wwenli@msm.edu
Prince
Chengyu Z
CZ
Hu
Xing
X
Pollman
Matthew J
MJ
D000818:Animals; D017209:Apoptosis; D051792:Basic Helix-Loop-Helix Proteins; D002455:Cell Division; D002460:Cell Line; D002470:Cell Survival; D002478:Cells, Cultured; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000378:metabolism; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D051381:Rats; D012097:Repressor Proteins / Q000502:physiology*; D015398:Signal Transduction
D051792:Basic Helix-Loop-Helix Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D012097:Repressor Proteins; C493958:Cdkn1a protein, rat; C405694:Hairy, HRT1 protein; C494920:Akt1 protein, rat