Ana M. Castejon

Endothelial nitric oxide synthase polymorphism, nitric oxide production, salt sensitivity and cardiovascular risk factors in Hispanics

Mutations in the endothelial nitric oxide synthase (eNOS) gene may be associated with abnormal nitric oxide (NO) production and cardiovascular diseases. In this study, we investigated the prevalence of two eNOS polymorphisms, the Glu298Asp variant on exon 7, and the 4a/b variable number of tandem repeats (VNTR) on intron 4, and their association with blood pressure (BP), NO production, salt sensitivity and cardiovascular risk factors in healthy Venezuelans. The prevalence of both polymorphisms in Venezuelans was comparable to that described for Caucasians, but significantly different from that known for African-Americans and Japanese. The 4a/b genotype was associated with reduced levels of NO metabolites (25% decrease), larger BP lowering in response to salt restriction (9.0 vs 4.8 mmHg, P<0.05), greater prevalence of salt sensitivity (39% in 4a/b and 27% in 4b/b; P<0.05) and with higher LDL-cholesterol levels. The Glu298T polymorphism did not affect NO production, nor it was associated with salt sensitivity. Glu298Asp polymorphism was positively associated with higher weight, triglycerides and LDL-cholesterol. Neither polymorphism was associated with changes in fasting or postload serum glucose, BP, obesity and albuminuria. In conclusion, the prevalence of eNOS polymorphisms is strongly determined by ethnic factors. The 4a/b gene polymorphism could be a genetic susceptibility factor for the BP response to salt intake and for the genetic control of NO production. The reduced NO production in subjects with the 4a/b genotype may be responsible for the increased sensitivity of their BP to salt.

Are Molecules Involved in Neuritogenesis and Axon Guidance Related to Autism Pathogenesis

Abstract Autism spectrum disorder is a heterogeneous disease, and numerous alterations of gene expression come into play to attempt to explain potential molecular and pathophysiological causes. Abnormalities of brain development and connectivity associated with alterations in cytoskeletal rearrangement, neuritogenesis and elongation of axons and dendrites might represent or contribute to the structural basis of autism pathology. Slit/Robo signaling regulates cytoskeletal remodeling related to axonal and dendritic branching. Components of its signaling pathway (ABL and Cdc42) are suspected to be molecular bases of alterations of normal development. The present review describes the most important mechanisms underlying neuritogenesis, axon pathfinding and the role of GTPases in neurite outgrowth, with special emphasis on alterations associated with autism spectrum disorders. On the basis of analysis of publicly available microarray data, potential biomarkers of autism are discussed.

Upregulation of angiotensin II-AT1 receptors during statin withdrawal in vascular smooth muscle cells.

Acute discontinuation of statins induces vascular dysfunction and increases cardiovascular events. The mechanisms underlying these events are under investigation. We showed an increase in angiotensin II (AngII) signaling after acute statin withdrawal. We investigated whether AngII-AT1-receptor expression (AT1-R mRNA) and receptor protein (AT1-R) levels mediate increased AngII signaling. In rat aortic vascular smooth muscle cells (VSMC), simvastatin (0.3 to 3 μM for 24 hours) resulted in concentration-dependent inhibition of AngII-stimulated phosphorylation of extracellular-signal regulated kinase 1/2 ERK1/2 (-67 ± 5% with 3 μM; P < 0.001) and decreased AT1-R mRNA (-34 ± 8% with 3 μM; P < 0.01) and AT1-R protein (-32 ± 6% with 3 μM; P < 0.01). Removal of simvastatin led to a rebound increase in mRNA-AT1-R (+39 ± 2%, P < 0.01), AT1-R protein (+46 ± 2%; P < 0.01), and AngII-mediated phosphorylation of ERK1/2 (+36 ± 3%; P < 0.01). The increase in receptor expression was present at 1 hour and lasted for 4 hours, whereas increased AT1-R protein and AngII signaling started at 2 hours and lasted for nearly 2 hours. In summary, increased AngII signaling after statin withdrawal is most likely due to increases in AT1-R number due to increased transcription. The increase in AngII activity may contribute to the vascular dysfunction associated with statin withdrawal.

A Community-Based Pilot Study of a Diabetes Pharmacist Intervention in Latinos: Impact on Weight and Hemoglobin A1c

Type 2 diabetes disproportionately affects Latinos increasing their risk of diabetes-related complications. This study used a randomized controlled design with a community-based approach to evaluate the impact of a culturally tailored pharmacist intervention on clinical outcomes in Latino diabetics. The intervention included a focused discussion and two individual pharmacist counseling sessions on medication, nutrition, exercise, and self-care to promote behavior changes. Sessions were culturally adapted for language, diet, family participation, and cultural beliefs. Clinical outcomes were measured at baseline and three months. Nineteen intervention and 24 control participants completed the study. Mean BMI reduction was greater for intervention than for control group participants (–0.73± 0.07 kg/m2 versus + 0.37±0.02 kg/m2 p<.009 respectively). Hemoglobin A1c was significantly reduced by 0.93±0.45% in the intervention group only. There was no significant difference in blood glucose, blood pressure, or lipid levels. An innovative culturally-sensitive pharmacist intervention improved selected clinical outcomes among Latino diabetics.