Crossveinless 2 regulates bone morphogenetic protein 9 in human and mouse vascular endothelium

The importance of morphogenetic proteins (BMPs) and their antagonists in vascular development is increasingly being recognized. BMP-4 is essential for angiogenesis and is antagonized by matrix Gla protein (MGP) and crossveinless 2 (CV2), both induced by the activin receptor like-kinase 1 (ALK1) when stimulated by BMP-9. In this study, however, we show that CV2 preferentially binds and inhibits BMP-9 thereby providing strong feedback inhibition for BMP-9/ALK1 signaling rather than for BMP-4/ALK2 signaling. CV2 disrupts complex formation involving ALK2, ALK1, BMP-4, and BMP-9 required for the induction of both BMP antagonists. It also limits VEGF expression, proliferation, and tube formation in ALK1-expressing endothelial cells. In vivo, CV2 deficiency translates into a dysregulation of vascular BMP signaling, resulting in an abnormal endothelium with increased endothelial cellularity and expression of lineage markers for mature endothelial cells. Thus, mutual regulation by BMP-9 and CV2 is essential in regulating the development of the vascular endothelium.     

Dipeptidyl peptidase 4 inhibitor sitagliptin protects endothelial function in hypertension through a glucagon-like Peptide 1-dependent mechanism

Sitagliptin, a selective dipeptidyl peptidase 4 inhibitor, inhibits the inactivation and degradation of glucagon like peptide 1 (GLP-1), which is used for the treatment of type 2 diabetes mellitus. However, little is known about the role of GLP-1 in hypertension. This study investigated whether the activation of GLP-1 signaling protects endothelial function in hypertension. Two-week sitagliptin treatment (10 mg/kg per day, oral gavage) improved endothelium-dependent relaxation in renal arteries, restored renal blood flow, and reduced systolic blood pressure in spontaneously hypertensive rats. In vivo sitagliptin treatment elevated GLP-1 and GLP-1 receptor expressions, increased cAMP level, and subsequently activated protein kinase A, liver kinase B1, AMP-activated protein kinase-α and endothelial NO synthase in spontaneously hypertensive rat renal arteries. Inhibition of GLP-1 receptor, adenylyl cyclase, protein kinase A, AMP-activated protein kinase-α, or NO synthase reversed the protective effects of sitagliptin. We also demonstrate that GLP-1 receptor agonist exendin 4 in vitro treatment had similar vasoprotective effects in spontaneously hypertensive rat renal arteries and increased NO production in spontaneously hypertensive rat aortic endothelial cells. Studies using transient expressions of wild-type and dominant-negative AMP-activated protein kinase-α2 support the critical role of AMP-activated protein kinase-α in mediating the effect of GLP-1 in endothelial cells. Ex vivo exendin 4 treatment also improved endothelial function of renal arteries from hypertensive patients. Our results elucidate that upregulation of GLP-1 and related agents improve endothelial function in hypertension by restoring NO bioavailability, suggesting that GLP-1 signaling could be a therapeutic target in hypertension-related vascular events.     

The association between seven ERAP1 polymorphisms and ankylosing spondylitis susceptibility: a meta-analysis involving 8,530 cases and 12,449 controls

Besides the MHC gene, HLA-B27, ERAP1 is one of the non-MHC genes which also play key roles in the pathogenesis of AS. It has been reported that there is an association between ERAP1 polymorphisms and AS Risk. However, the results were inconclusive. The aim of the current study was to determine the contribution of ERAP1 polymorphisms to ankylosing spondylitis (AS) susceptibility. To derive a more precise estimation of the association, a meta-analysis was performed by searching the MEDLINE and EMBASE data base. The crude odds ratios (ORs) with 95% confidence intervals (CIs) were calculated to access the strength of association between ERAP1 polymorphisms and AS risk. The pooled ORs were performed for minor allele versus major allele in all polymorphisms. Nine case–control studies consisting of 8,530 AS patients and 12,449 controls were identified in this meta-analysis. Except in rs27434 (P = 0.23), the significant correlation between ERAP1 polymorphisms and AS susceptibility has been detected in rs27044 (OR 1.57, P < 0.001), rs17482078 (OR 1.271, P < 0.001), rs10050860 (OR 0.772, P = 0.006), rs30187 (OR 1.348, P < 0.001), rs2287987 (OR 0.746, P < 0.001) and rs27037 (OR 1.257, P = 0.001). This meta-analysis demonstrates that the ERAP1 polymorphisms may play a significant role in susceptibility to AS. However, this result should be identified by more convincing experimental evidences in molecular level and population level.     

The natural plant product sophocarpine ameliorates dextran sodium sulfate-induced colitis in mice by regulating cytokine balance

Introduction  

Sophora alopecuroides L., a traditional Chinese herbal remedy, has been widely used for treating enteritis and bacillary dysentery for many years. Sophocarpine is a major ingredient of S. alopecuroides L. and has a wide range of pharmacological effects.