Role of ryanodine receptor 2 and FK506-binding protein 12.6 dissociation in pulmonary hypertension.
Yong-Xiao WangJorge Reyes-GarcíaAnnarita Di MiseYun-Min ZhengPublished in: The Journal of general physiology (2023)
Pulmonary hypertension (PH) is a devastating disease characterized by a progressive increase in pulmonary arterial pressure leading to right ventricular failure and death. A major cellular response in this disease is the contraction of smooth muscle cells (SMCs) of the pulmonary vasculature. Cell contraction is determined by the increase in intracellular Ca2+ concentration ([Ca2+]i), which is generated and regulated by various ion channels. Several studies by us and others have shown that ryanodine receptor 2 (RyR2), a Ca2+-releasing channel in the sarcoplasmic reticulum (SR), is an essential ion channel for the control of [Ca2+]i in pulmonary artery SMCs (PASMCs), thereby mediating the sustained vasoconstriction seen in PH. FK506-binding protein 12.6 (FKBP12.6) strongly associates with RyR2 to stabilize its functional activity. FKBP12.6 can be dissociated from RyR2 by a hypoxic stimulus to increase channel function and Ca2+ release, leading to pulmonary vasoconstriction and PH. More specifically, dissociation of the RyR2-FKBP12.6 complex is a consequence of increased mitochondrial ROS generation mediated by the Rieske iron-sulfur protein (RISP) at the mitochondrial complex III after hypoxia. Overall, RyR2/FKBP12.6 dissociation and the corresponding signaling pathway may be an important factor in the development of PH. Novel drugs and biologics targeting RyR2, FKBP12.6, and related molecules may become unique effective therapeutics for PH.
Keyphrases
- pulmonary hypertension
- pulmonary artery
- binding protein
- pulmonary arterial hypertension
- signaling pathway
- protein kinase
- oxidative stress
- multiple sclerosis
- coronary artery
- dna damage
- single cell
- endothelial cells
- stem cells
- smooth muscle
- cell therapy
- epithelial mesenchymal transition
- mesenchymal stem cells
- bone marrow
- case control