Novel signaling pathways and therapeutic options for pulmonary hypertension

Title : Novel signaling pathways and therapeutic options for pulmonary hypertension

Abstract:

Pulmonary hypertension (PH) is a common and devastating lung disease. The current primary medications for this disease are to use non-specific vasodilators, but patients do not always respond well to non-specific vasodilators. Voltage-dependent potassium channels and store-operated calcium channels may increase intracellular calcium concentration ([Ca²⁺]_i) in pulmonary arterial smooth muscle cells (PASMCs) to mediate the development of PH; however, experimental findings are uncertain. In a series of studies, we have explored the potential important role of ryanodine receptor 2 (RyR2) Ca²⁺ release channel in PH and its inhibition as therapeutic strategies for this disease. Our findings reveal that Rieske iron-sulfur protein (RISP) serves as a primary molecule to increase mitochondrial reactive oxygen species (ROS) generation, disassociate FKBP12.6 from RyR2, enhance the channel activity, and then induces calcium release from the sarcoplasmic reticulum (a major intracellular Ca²⁺ store), hereby causing PA vasoconstriction, remodeling, and ultimately hypertension. Moreover, the increased RISP-dependent ROS can also cause DNA damage to activate ataxia telangiectasia mutated (ATM) kinase, phosphorylate checkpoint kinases 2 (Chk2), and cause cell proliferation in PASMCs, leading to PA remodeling and hypertension. Our results further indicate that specific pharmacological and genetic RISP, RyR2, FKBP12.6 dissociation, ATM, and Chk2 inhibition may become specific and effective treatment options for PH and other relevant vascular diseases.

Biography:

Dr. Yong-Xiao Wang has been a Full Professor in Department of Molecular and Cellular Physiology at Albany Medical College since 2006. Dr. Wang obtained his MD at Wannan Medical University, PhD at Fourth Military Medical University, and postdoctoral training at Technology University of Munich as well as University of Pennsylvania. He has made many important findings using complementary molecular, biochemical, physiological, and genetic approaches at the molecular, organelle, cellular, tissue and organism levels in animals and human samples, had numerous publications in Nature Commun (impact factor: 14.290), Antioxid Redox Signal (8.209), Proc Natl Acad Sci USA (9.432), Nature (34.480), Circ Res (9.214), and other highly peer-reviewed journals and academic books, and served as the editorial board member and/or section editor as well as the executive committee member and/or subcommittee chair for professional societies.