Association between general and central adiposity and development of hypertension in early childhood.

OBJECTIVES: To evaluate the association of general and abdominal obesity with high blood pressure in young children. METHODS: A longitudinal study including 1796 participants from the Madrid region (Spain) with baseline at age 4 years and a follow-up 2 years later. Blood pressure, body mass index and waist circumference were measured during a physical examination. We evaluated the association between obesity at baseline and weight changes between the ages of 4 and 6 years and high blood pressure. Data were analysed using linear and logistic regressions adjusted for covariates. RESULTS: Obese 4 year olds (general or abdominal obesity) experienced an average 4-5 mmHg increase in systolic blood pressure and a 2.5-3 mmHg increase in diastolic blood pressure by the age of 6 years. Compared to children maintaining a non-excess weight (based on body mass index) during follow-up incident and persistent cases of excess weight (overweight or obesity) had an odds ratio (OR) for high blood pressure of 2.49 (95% confidence interval (CI) 1.50-4.13) and OR 2.54 (95% CI 1.27-5.07), respectively. Regarding abdominal obesity we estimated OR 2.81 (95% CI 0.98-8.02) for incident cases and OR 3.42 (95% CI 1.38-8.49) for persistent cases. Similar estimates for the waist-height ratio were observed. Individuals who experienced remission to non-excess weight did not have an increased risk of high blood pressure. CONCLUSIONS: We observed an increased risk for high blood pressure among 4-year-olds who presented with persistent or incident cases of excess weight (body mass index) or abdominal obesity after 2 years of follow-up. Children with excess weight or obesity at baseline who remitted to non-excess weight did not exhibit an increased risk of high blood pressure.

Effects of lysophosphatidic acid on calpain-mediated proteolysis of focal adhesion kinase in human prostate cancer cells.

BACKGROUND: Calcium-mediated proteolysis plays an important role in cell migration. Lysophosphatidic acid (LPA), a lipid mediator present in serum, enhances migration of carcinoma cells. The effects of LPA on calpain-mediated proteolysis were, therefore, examined in PC-3, a human prostate cancer cell line. METHODS: Cultured PC-3 cells were used in studies utilizing pharmacologic interventions, immunoblotting, and confocal immunolocalization. RESULTS: Focal adhesion kinase (FAK), a tyrosine kinase involved in cell adhesion, is rapidly proteolyzed in serum-starved PC-3 cells exposed to the calcium ionophore, ionomycin; Nck, p130CAS, PKCα, and Ras-GAP are also degraded. Thapsigargin, which causes more moderate increases in intracellular calcium, induces partial proteolysis of these proteins. Calpain inhibitors block the proteolytic responses to ionomycin and thapsigargin. Ionomycin does not induce proteolysis in cells maintained in serum, suggesting a protective role for growth factors contained in serum. LPA causes minor FAK proteolysis when added alone, but protects against ionomycin-induced proteolysis in a time-dependent manner. LPA also protects against the cell detachment that eventually follows ionomycin treatment. The response to LPA is blocked by an LPA receptor antagonist. A similar effect of LPA is observed in ionomycin-treated Rat-1 fibroblasts. In PC-3 cells, the protective effects of LPA and serum are correlated with phosphorylation and redistribution of paxillin, suggesting roles for phosphorylation-mediated protein-protein interactions. CONCLUSIONS: The complex effects of LPA on calpain-mediated proteolysis of FAK and other adhesion proteins are likely to play a role in the ability of LPA to promote attachment, migration, and survival of prostate cancer cells.

Signal transduction responses to lysophosphatidic acid and sphingosine 1-phosphate in human prostate cancer cells.

BACKGROUND: Lysophosphatidic acid (LPA) and sphingosine-1-phosphate (S1P) are lipid mediators that bind to G-protein-coupled receptors. In this study, signaling responses to 18:1 LPA and S1P were examined in parallel in three human prostate cancer cell lines: PC-3, Du145, and LNCaP. METHODS: Receptor expression was assessed by RT-PCR, Northern blotting, and immunoblotting. Cellular responses to mediators were studied by proliferation assays, phosphoprotein immunoblotting, and phospholipid metabolism assays. RESULTS: All cell lines express mRNA for both LPA and S1P receptors. PC-3 and Du145, but not LNCaP, proliferate in response to LPA and S1P. Epidermal growth factor (EGF), phorbol 12-myristate 13-acetate (PMA), LPA, and S1P induce activation of Erks in PC-3 and Du145; only EGF and PMA activate Erks in LNCaP. In Du145 and PC-3, Akt is activated by EGF, LPA, and S1P. Akt is constitutively active in LNCaP; EGF but not LPA or S1P stimulates further phosphorylation. FAK is phosphorylated in response to both LPA and S1P in PC-3 and Du145, but not in LNCaP. LPA and S1P stimulate phospholipase D (PLD) activity to varying extents in the different cell lines. Notably, both lipid mediators activate PLD in LNCaP. In Du145, LPA, but not S1P, activates PLD and enhances cellular production of LPA. CONCLUSIONS: Although both LPA and S1P induce signal transduction in all prostate cancer cell lines studied, a proliferation response is observed only when the Erk, Akt, and FAK pathways are activated. Other responses to the lipid mediators, such as PLD activation, likely contribute to other cellular outcomes.