Salt-inducible kinases: new players in pulmonary arterial hypertension?

Salt-inducible kinases (SIK1–3) are serine/threonine protein kinases that target several effector molecules implicated in the regulation of a variety of cellular processes including metabolism, inflammation, and cancer. Recent advances in the mechanistic understanding of pulmonary arterial hypertension (PAH) suggest a critical role for deregulated signaling pathways in patients and animal models. Multiple lines of evidence support functional parallels between SIK-regulated pathways in tumorigenesis, inflammation, and PAH. A better understanding of SIK functions and downstream targets may unlock the potential of SIKs as promising therapeutic targets for the development of much-needed therapies for PAH. Salt-inducible kinases (SIKs) are serine/threonine kinases belonging to the AMP-activated protein kinase (AMPK) family. Accumulating evidence indicates that SIKs phosphorylate multiple targets, including histone deacetylases (HDACs) and cAMP response element-binding protein (CREB)-regulated transcriptional coactivators (CRTCs), to coordinate signaling pathways implicated in metabolism, cell growth, proliferation, apoptosis, and inflammation. These pathways downstream of SIKs are altered not only in pathologies like cancer, systemic hypertension, and inflammatory diseases, but also in pulmonary arterial hypertension (PAH), a multifactorial disease characterized by pulmonary vasoconstriction, inflammation and remodeling of pulmonary arteries owing to endothelial dysfunction and aberrant proliferation of smooth muscle cells (SMCs). In this opinion article, we present evidence of SIKs as modulators of key signaling pathways involved in PAH pathophysiology and discuss the potential of SIKs as therapeutic targets for PAH, emphasizing the need for deeper molecular insights on PAH. Salt-inducible kinases (SIKs) are serine/threonine kinases belonging to the AMP-activated protein kinase (AMPK) family. Accumulating evidence indicates that SIKs phosphorylate multiple targets, including histone deacetylases (HDACs) and cAMP response element-binding protein (CREB)-regulated transcriptional coactivators (CRTCs), to coordinate signaling pathways implicated in metabolism, cell growth, proliferation, apoptosis, and inflammation. These pathways downstream of SIKs are altered not only in pathologies like cancer, systemic hypertension, and inflammatory diseases, but also in pulmonary arterial hypertension (PAH), a multifactorial disease characterized by pulmonary vasoconstriction, inflammation and remodeling of pulmonary arteries owing to endothelial dysfunction and aberrant proliferation of smooth muscle cells (SMCs). In this opinion article, we present evidence of SIKs as modulators of key signaling pathways involved in PAH pathophysiology and discuss the potential of SIKs as therapeutic targets for PAH, emphasizing the need for deeper molecular insights on PAH. heterotrimeric enzyme that functions as a cellular metabolic regulator and energy sensor. On ATP depletion, it inactivates anabolic ATP-consuming pathways and activates catabolic ATP-generating processes. It is also activated by several hormones and cytokines. Inactivates a number of metabolic enzymes involved in ATP-consuming cellular events including fatty acid, cholesterol and protein synthesis, and activates ATP-generating processes. increase CREB activity, promoting cell proliferation, differentiation, and metabolic switch, and for that reason play a key role in tumor progression and resistance to chemotherapy. repressors of transcription factors like MEF2, regulating physiological and pathological mechanisms such as those related to bone formation, vascular calcification, or leukemia. enzyme responsible for most of the NO produced in the vasculature. The NO is crucial for the regulation of vascular tone and cellular proliferation and migration, as well as leukocyte adhesion and platelet aggregation. Endothelial dysfunction associated with PAH is characterized by impaired NO production by eNOS. mechanism by which ECs lose cell-to-cell contact and undergo transition towards a mesenchymal-like phenotype. This comes with loss of endothelial markers, like vascular endothelial (VE)-cadherin and PECAM-1, and the gain of myofibroblast markers such α-SMA and vimentin. serine/threonine protein kinase that regulates cell metabolism, proliferation, and migration and is known to function as a tumor suppressor. transmembrane protein responsible for maintaining high cytosolic potassium concentration and low cytosolic sodium concentration. NKA is crucial to keep a negative resting membrane potential and provide a driving force for secondary ion transport, while it simultaneously works as a signal transducer in multiple pathways. Its expression and function are essential for the regulation of vasculature contractility. In pulmonary arteries, hypoxia inhibits NKA, leading to membrane depolarization and consequent opening of calcium channels, which culminates in vasoconstriction. a ubiquitous transcription factor that regulates the expression of genes involved in inflammation, innate immunity, stress responses, cell proliferation, and survival. Increased NF-κB activity promotes the expression of proinflammatory cytokines and chemokines, antiapoptotic factors, cell-cycle regulators, and adhesion molecules. NF-κB expression is increased in the lungs of PAH rodent models and activated in the pulmonary vessels of PAH patients. It is recognized as a key proinflammatory factor in the development of PAH.