Novel signaling mechanisms and innovative therapeutic strategies of pulmonary hypertension

Title : Novel signaling mechanisms and innovative therapeutic strategies of pulmonary hypertension

Abstract:

Chronic obstructive pulmonary disease (COPD) is a serious lung disease with a high prevalence and mortality. The current therapeutics for this disease are neither specific nor very effective. This problem is highly associated with our incomplete understanding of the cellular responses and molecular mechanisms of COPD. This severe disease is well characterized by airway hyperresponsiveness and remodeling, thereby leading to airflow limitation. A very important player in airway hyperresponsiveness and remodeling in COPD is an increase in intracellular calcium ([Ca²⁺]_i) in airway smooth muscle cells (ASMCs). [Ca²⁺]_i is well generated and controlled by multiple ion channels. In the current studies, we have first started to explore which type of ion channels may mediate the increased [Ca²⁺]_i in ASMCs and COPD. Using the patch clamp recording, the Nobel Prize winners’ technology, together with specific channel antibodies, we have found that type-3 canonical transient receptor potential (TRPC3) non-selective cation channel, showed a predominant activity and expression among the entire TRPC channel family in ASMCs. Similarly, using the SMC promoter SM22α-driven TRPC3 channel shRNAs, we confirmed the predominant TRPC3 channel activity and increased [Ca²⁺]_i in ASMCs. This channel protein expression was significantly increased in COPD human ASMCs. The increased TRPC3 channel expression was highly correlated with ASM remodeling in COPD. In support, proliferation of human COPD ASMCs was abolished by the specific channel inhibitor Pyr3. Like Pyr3, TRPC3 channel gene knockdown (KD) by its specific shRNAs also blocked the increased proliferation of COPD human ASMCs. In contrast, TRPC3 channel gene overexpression produced an opposite effect. It is known that pulmonary artery hypertension (PAH) is a common complication of COPD. The prevalence of PH can be up to 70% of COPD. Similar to the increased airway SMC cellular responses in COPD, PA vasoconstriction and remodeling both occur in PAH. A series of studies have shown that a significant disassociation of FK506 binding protein 12.6 (FKBP12.6) from type-2 ryanodine receptor (RyR2) Ca²⁺ release channel on the sarcoplasmic reticulum (SR, a major intracellular Ca²⁺ store) in PASMCs, RyR2 channel activity, Ca²⁺ release from the SR in PASMCs, and subsequent PA vasoconstriction, remodeling, and PAH. Moreover, FKBP12.6/RyR2 dissociation is a result of the increased Rieske iron-sulfur protein (RISP)-dependent mitochondrial ROS. The specific pharmacological and/or genetic RyR2 channel and RISP inhibition block the development of PAH.

Biography:

Dr. Wang has been a Full Professor at Albany Medical College since 2006. He had his MD, PhD and extensive postdoctoral training. Dr. Wang’s research projects have been supported by a number of research awards from NIH, American Heart Association, American Diabetes Association, American Lung Association, and other agencies. He has had numerous publications in Nature Commun (impact factor: 17.694), Antioxid Redox Signal (8.401), Proc Natl Acad Sci USA (12.779), Nature (69.504), Circ Res (23.218), and other highly peer-reviewed journals. Moreover, Dr. Wang has served as the editorial board member, section editor, and the executive committee member and/or subcommittee chair.