Cyclin D1 degradation enhances endothelial cell survival upon oxidative stress

Abstract

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.

miR-200c is upregulated by oxidative stress and induces endothelial cell apoptosis and senescence via ZEB1 inhibition

“…In keeping with previous studies from our 7,8,24 and other laboratories, 25,26 H 2 O 2 concentrations used in this paper are within the submillimolar range, and induce negligible EC death in vitro. Therefore the red/ox imbalance achieved is likely close to what is expected to occur in many pathophysiological conditions, for example, reperfusion injury, when oxidative stress induces extensive cell death and organ failure.…”

“…3 miR-200 family has been extensively studied in the epithelial-to-mesenchimal transition (EMT) of cancer cells; 14 in EMT miR-200 family downmodulation enhances cancer aggressiveness and metastases, whereas reintroduction of miR-200 family miRNAs in some tumors inhibits their growth. 14 As ROS inhibit cell proliferation, 7,8,24 we wanted to establish whether some effects of oxidative stress on cell function could be due to miR-200c upregulation.…”

Expression Profiling and Biochemical Analysis Suggest Stress Response as a Potential Mechanism Inhibiting Proliferation of Polyamine-depleted Cells

“…Cell Cycle Inhibition by Polyamine Depletion-Growth arrest can be manifested as a result of reduced availability of growthstimulating proteins such as cyclin D1, whose level was previously demonstrated to decline rapidly in stressed cells due to attenuated translation and accelerated degradation (40,51,52). We demonstrate here that the level of the cyclin D1 protein declines in DFMO-treated cells (Fig.…”

Hydrogen Peroxide Induces Cell Cycle Arrest in Cardiomyoblast H9c2 Cells, Which Is Related to Hypertrophy

“…15,24,25) and Ca 2ϩ participates in several pathways that induce cell cycle arrest. 15,24) Santini et al found that the calcineurin/nuclear factor of activated T-cell (NFAT) pathway, which is activated by intracellular Ca 2ϩ and induces p21 expression, is involved in cell cycle arrest during keratinocyte differentiation induced by the addition of Ca 2ϩ . 47) Our results together with others findings suggest that an increase in intracellular Ca 2ϩ is involved in p21 expression, resulting in cell cycle arrest in H 2 O 2 -treated H9c2 cells.…”