Cyclin D1 degradation enhances endothelial cell survival upon oxidative stress.
The understanding of endothelial cell responses to oxidative stress may provide insights into aging mechanisms and into the pathogenesis of numerous cardiovascular diseases. In this study, we examined the regulation and the functional role of cyclin D1, a crucial player in cell proliferation and survival. On H2O2 treatment, endothelial cells showed a rapid down-modulation of cyclin D1. Other D-cyclins were similarly regulated, and this decrease was also observed after exposure to other oxidative stress-inducing stimuli, namely 1,3-bis (2 chloroethyl)-1 nitrosourea treatment and ischemia. H2O2 treatment induced cyclin D1 ubiquitination followed by proteasome degradation. Phospholipase C inhibition prevented cyclin D1 degradation, and its activation triggered cyclin D1 down-modulation in the absence of oxidative stress. Activated phospholipase C generates inositol-1,4,5-trisphosphate (IP3) and Ca2+ release from internal stores. We found that both IP3-receptor inhibition and intracellular Ca2+ chelation prevented cyclin D1 degradation induced by oxidative stress. Furthermore, Ca2+ increase was transduced by Ca2+/calmodulin-dependent protein kinase (CaMK). In fact, H2O2 stimulated CaMK activity, CaMK inhibitors prevented H2O2-induced cyclin D1 down-modulation, and CaMK overexpression induced cyclin D1 degradation. Finally, overriding of cyclin D1 down-modulation via its forced overexpression or via CaMK inhibition increased cell sensitivity to H2O2-induced apoptotic cell death. Thus, cyclin D1 degradation enhances endothelial cell survival on oxidative stress.
Fasanaro
Pasquale
P
Istituto Dermopatico dell'Immacolata-IRCCS, Via dei Monti di Creta 104, Rome 00167, Italy.
Magenta
Alessandra
A
Zaccagnini
Germana
G
Cicchillitti
Lucia
L
Fucile
Sergio
S
Eusebi
Fabrizio
F
Biglioli
Paolo
P
Capogrossi
Maurizio C
MC
Martelli
Fabio
F
D017209:Apoptosis; D002118:Calcium / Q000378:metabolism; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D002470:Cell Survival; D019938:Cyclin D1 / Q000378:metabolism*; D015536:Down-Regulation; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D004730:Endothelium, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D018384:Oxidative Stress; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D010738:Type C Phospholipases / Q000378:metabolism; D025801:Ubiquitin / Q000378:metabolism
D025801:Ubiquitin; D019938:Cyclin D1; D006861:Hydrogen Peroxide; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D010738:Type C Phospholipases; D046988:Proteasome Endopeptidase Complex; D002118:Calcium