Title : Innovative mechanisms, consequences and therapeutics for pulmonary hypertension
Abstract:
Currently, pulmonary hypertension (PH) is a widespread lung disease, molecular mechanisms remain poorly understanded, and medications are neither always effective nor specific. In a series of our present studies, we have explored the potential important role of ryanodine receptor 2 (RyR2) Ca2+ release channel in the development of PH. Moreover, we have also investigated whether its inhibitory blockers and biologics may block this devastating 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 PASMC proliferation, PA vasoconstriction and remodeling, and ultimately PH. Moreover, the increased RISP-dependent ROS can also cause DNA damage to activate ataxia telangiectasia mutated (ATM) kinase, phosphorylate checkpoint kinases 2 (Chk2), further PASMC proliferation, and further PA remodeling and PH.
Taken together, our results demonstrate that RISP, FKBP12.6, RyR2, ATM, and Chk2 work as a successive signaling pathway to mediate PH. Furthermore, specific inhibitory blockers and biologics of the molecules as described here may become innovative and effective treatment options for PH and other relevant vascular diseases.
