Citations

M-atrial natriuretic peptide (ANP; M-ANP) is a novel next generation 40 amino acid peptide based on ANP, which is highly resistant to enzymatic degradation and has greater and more sustained beneficial actions compared with ANP. The current study was designed to advance our understanding of the therapeutic potential of M-ANP in a canine model of acute angiotensin II–induced hypertension with elevated cardiac filling pressures and aldosterone activation. We compare M-ANP with vehicle and equimolar human B-type natriuretic peptide, which possesses the most potent in vivo actions of the native natriuretic peptides. M-ANP significantly lowered mean arterial pressure and systemic vascular resistance. Importantly, despite a reduction in blood pressure, renal function was enhanced with significant increases in renal blood flow, glomerular filtration rate, diuresis, and natriuresis after M-ANP infusion. Although angiotensin II induced an acute increase in pulmonary capillary wedge pressure, M-ANP significantly lowered pulmonary capillary wedge pressure, pulmonary artery pressure, and right atrial pressure. Further, M-ANP significantly suppressed angiotensin II–induced activation of aldosterone. These cardiovascular and renal enhancing actions of M-ANP were accompanied by significant increases in plasma and urinary cGMP, the second messenger molecule of the natriuretic peptide system. When compared with human B-type natriuretic peptide, M-ANP had comparable cardiovascular actions but resulted in a greater natriuretic effect. These results suggest that M-ANP, which is more potent than ANP in normal canines, has potent blood pressure lowering and renal enhancing properties and may, therefore, serve as an ANP based therapeutic for acute hypertension.

<div class="htmlview paragraph">A methodical investigation and measurement of human dynamic response to impact acceleration is being conducted as a Joint Army-Navy-Wayne State University investigation. Details of the experimental design were presented at the Twelfth Stapp Car Crash Conference in October 1968.</div> <div class="htmlview paragraph">Linear accelerations are being measured on the top of the head, at the mouth, and at the base of the neck. Angular velocity is also being measured at the base of the neck and at the mouth. A redundant photographic system is being used for validation. All data are collected in computer compatible format and data processing is by digital computer. Selected data in a stage of interim analysis on 18 representative human runs of the 236 human runs completed to date are presented.</div> <div class="htmlview paragraph">Review of the data indicates that peak accelerations measured at the mouth are higher than previous estimates. The time relationship of the peak resultant mouth accelerations to the peak sled acceleration for this particular accelerator and restraint system is described. The maximum peak resultant mouth acceleration was 47.8 g and the peak mouth angular velocity on another run exceeded 30 rad/sec, on nominal 10 g, 250 g/sec runs. Clinical evaluation of the subjects before and after the runs disclosed no evidence of unconsciousness or neurological deficit attributable to the acceleration.</div> <div class="htmlview paragraph">Representative plots of the human dynamic response are presented, discussed, and compared. A first-order linear regression analysis for the peak mouth resultant acceleration and the peak mouth angular velocity obtainable from the peak sled acceleration is presented.</div>

Abstract Early B cell factor (EBF) is a transcription factor essential for specification and commitment to the B cell fate. In this study, we show downregulation of a developmentally regulated cluster of hoxa genes, notably hoxa9, coincides with induction of EBF at the Pro-B cell stage of B cell differentiation. Analysis of the hematopoietic progenitor compartment in Hoxa9−/− mice revealed significantly reduced frequencies and expression levels of Flt3, a cytokine receptor important for lymphoid priming and the generation of B cell precursors (BCPs). We show that Hoxa9 directly regulates the flt3 gene. Chromatin immunoprecipitation analysis revealed binding of Hoxa9 to the flt3 promoter in a lymphoid progenitor cell line. Knockdown of Hoxa9 significantly reduced Flt3 transcription and expression. Conversely, forced expression of Hoxa9 increased Flt3 transcription and expression in a Pro-B cell line that expressed low levels of Flt3. Hoxa9 inversely correlated with ebf1 in ex vivo-isolated bone marrow progenitors and BCPs, suggesting that EBF might function to silence a Hoxa9 transcriptional program. Restoration of EBF function in an EBF−/− cell line induced B lineage gene expression but did not directly suppress hoxa9 transcription, revealing alternate mechanisms of Hoxa9 regulation in BCPs. These data provide new insight into Hoxa9 function and regulation during lymphoid and B cell development. Furthermore, they suggest that failure to upregulate Flt3 provides a molecular basis for the lymphoid/early B cell deficiencies in Hoxa9−/− mice.

Rationale: Activity of the large conductance Ca 2+ -activated K + (BK) channels is profoundly modulated by its β 1 subunit (BK-β 1 ). However, BK-β 1 expression is downregulated in diabetic vessels. The ubiquitin–proteasome system (UPS) is a major mechanism of intracellular protein degradation. Whether UPS participates in BK-β 1 downregulation in diabetic vessels is unknown. Objective: We hypothesize that UPS facilitates vascular BK-β 1 degradation in diabetes. Methods and Results: Using patch clamp and molecular biological approaches, we found that BK-β 1 –mediated channel activation and BK-β 1 protein expression were reduced in aortas of streptozotocin-induced diabetic rats and in human coronary arterial smooth muscle cells (CASMCs) cultured in high glucose. This was accompanied by upregulation of F-box only protein (FBXO)-9 and FBXO-32 (atrogin-1), the key components of the Skp1-Cullin-F-box (SCF) type ubiquitin ligase complex. BK-β 1 expression was suppressed by the FBXO activator doxorubicin but enhanced by FBXO-9 small interfering RNA or by the proteasome inhibitor MG-132. Cotransfection of atrogin-1 in HEK293 cells significantly reduced Flag-hSlo-β 1 expression by 2.16-fold, compared with expression of Flag-hSlo-β 1 V146A (a mutant without the PDZ-binding motif). After cotransfection with atrogin-1, the ubiquitination of Flag-hSlo-β 1 was increased by 1.91-fold, compared with that of hSlo-β 1 V146A, whereas cotransfection with atrogin-1ΔF (a nonfunctional mutant without the F-box motif) had no effect. Moreover, inhibition of Akt signaling attenuated the phosphorylation of forkhead box O transcription factor (FOXO)-3a and enhanced atrogin-1 expression, which in turn suppressed BK-β 1 protein levels in human CASMCs. Conclusions: Downregulation of vascular BK-β 1 expression in diabetes and in high-glucose culture conditions was associated with FOXO-3a/FBXO-dependent increase in BK-β 1 degradation.