In response to stroke, astrocytes become reactive astrogliosis and are a major component of a glial scar. This results in the formation of both a physical and chemical (production of chondroitin sulfate proteoglycans) barrier, which prevent neurite regeneration that, in turn, interferes with functional recovery. However, the mechanisms of reactive astrogliosis and glial scar formation are poorly understood. In this work, we hypothesized that repulsive guidance molecule a (RGMa) regulate reactive astrogliosis and glial scar formation. We first found that RGMa was strongly expressed by reactive astrocytes in the glial scar in a rat model of middle cerebral artery occlusion/reperfusion. Genetic or pharmacologic inhibition of RGMa in vivo resulted in a strong reduction of reactive astrogliosis and glial scarring as well as in a pronounced improvement in functional recovery. Furthermore, we showed that transforming growth factor β1 (TGFβ1) stimulated RGMa expression through TGFβ1 receptor activin-like kinase 5 (ALK5) in primary cultured astrocytes. Knockdown of RGMa abrogated key steps of reactive astrogliosis and glial scar formation induced by TGFβ1, including cellular hypertrophy, glial fibrillary acidic protein upregulation, cell migration, and CSPGs secretion. Finally, we demonstrated that RGMa co-immunoprecipitated with ALK5 and Smad2/3. TGFβ1-induced ALK5-Smad2/3 interaction and subsequent phosphorylation of Smad2/3 were impaired by RGMa knockdown. Taken together, we identified that after stroke, RGMa promotes reactive astrogliosis and glial scar formation by forming a complex with ALK5 and Smad2/3 to promote ALK5-Smad2/3 interaction to facilitate TGFβ1/Smad2/3 signaling, thereby inhibiting neurological functional recovery. RGMa may be a new therapeutic target for stroke.

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The prevalence of type II diabetes mellitus (T2DM) in coronary artery disease (CAD) patients has been steadily increasing, especially in East Asian countries. Although many studies have suggested that certain genetic variants may predispose to the development of T2DM, very few studies investigated the genetic link with T2DM in CAD patients of East Asia. In this study, we investigated the relationship between Glu504Lys polymorphism in the acetaldehyde dehydrogenase 2 (ALDH2) gene, a key enzyme of alcohol metabolism, and the risk of having T2DM in Chinese Han CAD patients. We enrolled 542 CAD patients (180 women and 362 men) and 309 CADÀ/DMÀ subjects (152 women and 157 men). T2DM was confirmed in 47.4% of CAD patients. Logistic and linear regression analyses showed that ALDH2 mutant genotypes (*1/*2 and *2/*2) were an independent risk factor for both T2DM in female CAD patients, even after controlling for alcohol consumption (OR¼1.95, P¼0.043), and fasting plasma glucose (FPG) in CADÀ/DMÀ women (P¼0.015), whereas the association with FPG disappeared after controlling for high-sensitivity C-reactive protein, a classic inflammatory biomarker. However, there was no relationship between the ALDH2 genetic polymorphism and T2DM or FPG in men. These findings suggest that the ALDH2 polymorphism is associated with an increased risk of T2DM in female CAD patients, and this association could be causal on the basis of the association between the polymorphism and FPG, which is partly explained by an increased inflammatory status. These findings will benefit the screening and treatment of a high-risk population in East Asians.

Our finding demonstrates that HPV-16 E7 down-regulates surface HLA class I antigen, which in part correlates with the decrease of TAP-1.