Dr. Yang Xia
The University of Texas Health Science Center at Houston
Department of Biochemistry and Molecular Biology
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 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. Our studies are the first to provide direct evidence that preeclampsia may be a pregnancy-induced autoimmune disease in which key features of the disease result from AT1-AA (Fig.1). 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.
II. Adenosine signaling, priapism and sickle cell disease
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.
Priapism is defined as prolonged penile erection unassociated with sexual interest. 40% of male sickle cell disease (SCD) patients display priapism. The disorder is dangerous and urgent given its association with erectile tissue damage and erectile dysfunction. Current strategies to manage the disorder are poor due to lack of fundamental understanding of the pathophysiology of priapism.
Recently my laboratory unexpectedly found that male adenosine deaminase (ADA)-deficient mice display features of priapism seen in humans, including spontaneous prolonged penile erection with subsequent penile fibrosis. In addition, we demonstrated that reducing the accumulation of adenosine by ADA enzyme therapy relieved spontaneous prolonged penile erection and relaxation both in vivo and in vitro, suggesting that increased adenosine contributes to priapism and immediate therapeutic possibility. Moreover, the analysis of four adenosine receptor deficient mice revealed that the A2BR is essential for adenosine-mediated cavernosal smooth muscle relaxation and that up-regulated A2BR signaling contributes to priapic activity in ADA-deficient mice. Finally we found that priapic activity in the SCD transgenic mouse, a well accepted priapic animal model, is also due to elevated adenosine signaling via A2BR, suggesting a general contributory role of adenosine and A2BR signaling in priapism.
To our surprise, lowering adenosine concentrations by PEG-ADA enzyme therapy also significantly reduces sickling and multiple organ damages/dysfunction in SCD Tg mice. These findings led us to further discover that elevated adenosine signaling through the A2B adenosine receptor promotes sickling by induction 2,3-diphosphoglycerate (2,3-DPG), an erythroid specific molecule known to promote O2 release. More importantly, we demonstrated that adenosine is also increased in the blood circulation of SCD patients and contributes to sickling via A2BR-mediated 2,3-DPG induction. Thus, our findings reveal a detrimental role of adenosine signaling in SCD and provide novel therapeutic possibilities to treat and prevent sickling and progression to multiple life-threatening complications.
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.
Biochemistry and Molecular Biology
Office: MSB 6.206
Ph.D. - The University of Texas Graduate School of Biomedical Sciences at Houston - 1998
M.D. - Hunan Medical University - 1992