Title : Novel mechanisms and new therapeutics for right heart failure in pulmonary hypertension
Abstract:
Right ventricular remodeling and associated right heart failure (RHF) are common and severe cardiovascular diseases. These diseases often occur in pulmonary hypertension (PH). PH and associated RHF are widespread devastating diseases. Their molecular responses and mechanisms remain poorly understanded, and medications are neither always effective nor specific. In a series of recent 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, PASMC proliferation, and PA remodeling and PH. Altogether, our results demonstrate that RISP, FKBP12.6, RyR2, and ATM work as a successive signaling pathway to mediate PH and RHF. Furthermore, specific inhibitory blockers and biologics of the molecules as described here may become innovative and effective treatment options for PH, RHF, and other relevant vascular diseases.
