Dr. Yang Xia, Associate Professor

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molecular basis of cardiovascular diseases

My laboratory has two research projects focusing on molecular mechanisms of vascular diseases.

I. Angiotensin receptors, autoimmunity and preeclampsia
Preeclampsia featured with hypertension, proteinuria and endothelial dysfunction affects approximately 5% of pregnancies and remains a leading cause of maternal and neonatal mortality and morbidity in the United States and the world. The clinical management of preeclampsia is hampered by the lack of pre-symptomatic screening, reliable diagnostic tests and effective therapy.

We have recently shown that key features of preeclampsia, including hypertension, proteinuria, placental abnormalities (including increased secretion of anti-angiogenic factors) and small fetuses appeared in pregnant mice following injection with either total IgG or affinity purified angiotension receptor agonist autoantibody (AT₁-AA) from women with preeclampsia. These features were prevented by co-injection with losartan, an AT₁ receptor antagonist or by an antibody neutralizing seven-amino acid (7-aa) epitope peptide. Extending these animal studies to human studies, we have recently shown that AT₁-AAs are highly prevalent in PE (>95%) and that antibody titers strongly correlate to the severity of the disease. These clinical studies significantly extend our animal studies and add support to our working hypothesis that PE contains an autoimmune component characterized by the presence of disease-causing autoantibodies. Our long-term goal is to determine the molecular mechanism of AT₁-AA in pathophysiology of preeclampsia and immunological cause of AT₁-AA and develop a novel diagnostic and therapeutic possibility for the disease.

Fig.1 AT₁-AA induces preeclampsia in pregnant mice, suggesting a novel hypothesis that preeclampsia is a gestational-induced autoimmune disease. Testing this hypothesis is the one of the major goals in my lab as proposed in this application.

II. Metabolites, sickle cell disease and novel therapeutics

Sickle cell disease (SCD) is a devastating inherited hemolytic disorder that affects red blood cells (RBCs) due to a single point mutation which results in the substitution of valine for glutamic acid at sixth position of the β-globin chain of hemoglobin. Despite our precise knowledge of the molecular defect associated with sickle hemoglobin (HbS) in RBCs, we still lack preventative approaches or mechanism-specific treatment options for the disease due to poor understanding the molecular events controlling HbS polymerization and erythrocyte sickling, processes which are central to the pathogenesis of the disease.
Although SCD initiates from erythrocyte sickling, it quickly develops into a multi-cellular and systemic disorder characterized by intravascular hemolysis, inflammation, complement activation, platelet activation, endothelial dysfunction and eventually progresses to vaso-occlusion featured with pulmonary arterial hypertension and severe pain. Thus, specific factors released from sickled erythrocytes as a result of hemolysis, may drive multiple downstream cellular events that contribute to disease. To identify the potential circulating factors released from RBCs in SCD, we took a novel approach to conduct a non-biased high throughput metabolomic screen. Among 7000 small metabolites screened, adenosine (Ado) and 2,3-diphosphoglycerate (2.3-DPG) are highly elevated in the erythrocytes and plasma of humans and mice with SCD. Using pharmacological, genetic, cellular and biochemical approaches, we revealed that elevated Ado signaling through the A_2B adenosine receptor (A_2BR) promoted sickling by the induction of 2,3-DPG, an erythrocyte specific molecule known to decrease hemoglobin O₂ binding affinity (Fig.2). Our recently published studies about the detrimental effect of Ado signaling in SCD have provided promising opportunities for clinical trials in SCD patients in the near future.
In addition to our evidence for the detrimental effects of elevated Ado in SCD we now have identified multiple metabolites altered in the circulation of both SCD patients and mice and likely play an important role in pathogenesis of SCD. These molecules include bioactive lipids, lysophospholipids, free fatty acids and amino acids. Taken together, our innovative metabolomic screening combined with a multidisciplinary approach has led us to successfully identify the detrimental effects of several metabolite signaling molecules in SCD pathophysiology. Our findings provide a new concept of altered metabolites in pathogenic nature of the disease and immediately open up possibilities to treat SCD patients by targeting on these newly identified metabolite signaling molecules. Therefore, the innovation of our studies is represented by novel therapeutic opportunities that were revealed by the results of a metabolomic screen and multidisciplinary approaches.
We have acquired significant research experience in most areas of biochemistry, molecular genetics, physiology, histology and vascular biology needed to determine the molecular mechanism underlying these two dangerous vascular diseases. These studies will provide the potential therapeutic possibility for the disease.

Fig. 2. Role of adenosine signaling in sickling and multiple tissue damages by A2BR-mediated 2,3-DPG induction.

Selected References