Faculty Bibliography

Insulin resistance, a major factor in the development of type 2 diabetes, is known to be associated with defects in blood vessel relaxation. The role of Akt on insulin-induced relaxation of vascular smooth muscle cell (VSMC) was investigated using siRNA targeting Akt (siAKTc) and adenovirus constructing myristilated Akt to either suppress endogenous Akt or overexpress constitutively active Akt, respectively. siAKTc decreased both basal and insulin-induced phosphorylations of Akt and glycogen synthase kinase 3beta, abolishing insulin-induced nitric oxide synthase (iNOS) expression. cGMP-dependent kinase 1alpha (cGK1alpha) and myosin-bound phosphatase (MBP) activities, both downstream of iNOS, were also decreased. siAKTc treatment resulted in increased insulin and ANG II-stimulated phosphorylation of contractile apparatus, such as MBP substrate (MYPT1) and myosin light chain (MLC20), accompanied by increased Rho-associated kinase alpha (ROKalpha) activity, demonstrating the requirement of Akt for insulin-induced vasorelaxation. Corroborating these results, constitutively active Akt upregulated the signaling molecules involved in insulin-induced relaxation such as iNOS, cGK1alpha, and MBP activity, even in the absence of insulin stimulation. On the contrary, the contractile response involving the phosphorylation of MYPT1 and MLC20, and increased ROKalpha activity stimulated by ANG II were all abolished by overexpressing active Akt. In conclusion, we demonstrated here that insulin-induced VSMC relaxation is dependent on Akt activation via iNOS, cGK1alpha, and MBP activation, as well as the decreased phosphorylations of MYPT1 and MLC20 and decreased ROKalpha activity.

OBJECTIVES/OBJECTIVE:Using serum neopterin as a marker of macrophage activation, we sought to examine the relationship between serum neopterin levels, thrombolysis in myocardial infarction (TIMI) risk scores, and how different treatments of acute coronary syndromes affect change in neopterin. METHODS:We examined serum neopterin concentrations at presentation and 72 h after treatment in 70 patients with acute coronary syndromes (35 with medical therapy, 25 with uncoated coronary stents, and 10 received rapamycin-eluting stents) using a commercially available immunoassay. Serum neopterin levels were determined for 36 patients with stable coronary artery disease. TIMI risk scores were calculated when appropriate (n=58). RESULTS:Serum neopterin had a strong correlation with the TIMI risk score on admission (P<0.0001). The mean baseline neopterin levels in patients with acute coronary syndromes stratified with TIMI scores between 1 and 7 were the following: patients with TIMI 1 scores had a level of 3.3+/-0.4 nmol/l, TIMI 2 patients 4.6+/-0.6 nmol/l, TIMI 3 patients 5.5+/-1.4 nmol/l, TIMI 4 patients 7.5+/-2.4 nmol/l, TIMI 5 patients 10.8+/-3.3 nmol/l, TIMI 6 patients 17.5+/-4.0 nmol/l, and TIMI 7 patients 23.0+/-7.1 nmol/l. Mean changes in serum neopterin were significantly higher for the uncoated stent group than for each of the other three groups (P<0.05). CONCLUSIONS:Serum neopterin concentrations have a high correlation with TIMI risk scores and may represent a marker useful in stratifying patients with acute coronary syndromes. Our results also suggest that the use of uncoated coronary stents results in macrophage activation not found with other treatment modalities.

Complex genetic and environmental mechanisms of maternal, fetal and placental origin regulate fetal growth and may contribute to fetal growth restriction (FGR). The somatotrophic regulatory factors include IGF-I, IGF-II, the IGF binding proteins (IGFBP) 1-6, IGF receptors 1 and 2, and the IGFBP specific proteases. Abnormal remodeling of utero-placental arteries and abnormal fetal-placental angiogenesis has also been implicated in FGR. The underlying molecular mediators include vascular endothelial growth factor (VEGF), placental growth factor (PlGF), VEGF receptors, VEGF binding proteins, and numerous other agents working through multiple pathways many of which still remain unknown. Expression of these major angiogenic factors appears to be regulated by local oxygen partial pressure. Future investigations may resolve many of these issues not only adding to the clarity of our understanding of the mechanisms of growth restriction but also improving clinical management.