title: Distinct Effects of Inorganic Phosphate on Cell Cycle and Apoptosis in Human Vascular Smooth Muscle Cells.
abstract: Inorganic phosphate (Pi) is an essential nutrient to all living organisms. Nevertheless, hyperphosphatemia is now recognized as a risk factor for cardiovascular events and mortality in chronic kidney disease (CKD) patients. To our knowledge, the mechanisms by which elevated Pi alters smooth muscle cell proliferation have been poorly addressed. Therefore, in this study, we investigated the effects of Pi on cell cycle regulation and apoptosis in human aortic smooth muscle cells (HAoSMC). HAoSMC were treated with physiologic (1 mM) or high (2 and 3 mM) Pi concentrations. We showed that Pi not only decreased significantly cell viability (P < 0.001) but also induced apoptosis of HAoSMC. Moreover, Pi treatment blocked G1/S cell cycle progression by increasing cell number in G0/G1 phase up to 82.4 ± 3.4% for 3 mM vs 76.2 ± 3.1% for control (P < 0.01) while decreasing cell number in S phase. Accordingly, this was associated with a decrease protein expression of cyclin E and its associated CDK (CDK2), and phosphorylated retinoblastoma protein. Moreover, we observed an increase of protein expression of cell cycle inhibitors p15, p21, and p27. Interestingly, we also found that induction of cell cycle arrest was partially dependent on phosphate uptake. Our results demonstrated that Pi reduced HAoSMC proliferation by inducing apoptosis and cell cycle arrest. Indeed, we showed for the first time that Pi affected HAoSMC cell cycle by blocking G1/S progression. These findings would be useful for a better understanding of molecular mechanisms involved in vascular complications observed in CKD patients.
authors: Inserm U1088, Université de Picardie Jules Verne, Amiens, France.
authors: Haifa
authors: H
authors: Rahabi-Layachi
authors: HERVI EA3801, Université de Picardie Jules Verne, UFR de Médecine, Amiens, France.
authors: Roger
authors: R
authors: Ourouda
authors: Inserm U1088, Université de Picardie Jules Verne, Amiens, France.|Centre de Biologie Humaine, CHU Amiens, Amiens, France.|Laboratoire de Biochimie, CHU Amiens, Amiens, France.
authors: Agnes
authors: A
authors: Boullier
authors: Inserm U1088, Université de Picardie Jules Verne, Amiens, France.|Nephrology Division CHU Ambroise Paré, Avenue Charles de Gaulle, Boulogne-Billancourt, France.
authors: Ziad A
authors: ZA
authors: Massy
authors: HERVI EA3801, Université de Picardie Jules Verne, UFR de Médecine, Amiens, France.|Centre de Biologie Humaine, CHU Amiens, Amiens, France.
authors: Carole
authors: C
authors: Amant
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D002453:Cell Cycle / Q000187:drug effects*; D018797:Cell Cycle Proteins / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects* / Q000502:physiology; D049109:Cell Proliferation / Q000187:drug effects; D018844:Cyclin-Dependent Kinases / Q000378:metabolism; D016213:Cyclins / Q000378:metabolism; D006801:Humans; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000378:metabolism; D010710:Phosphates / Q000378:metabolism / Q000494:pharmacology*; D016160:Retinoblastoma Protein / Q000378:metabolism
chemical_list: D018797:Cell Cycle Proteins; D016213:Cyclins; D010710:Phosphates; D016160:Retinoblastoma Protein; D018844:Cyclin-Dependent Kinases