Hypoxia-induced signaling in the cardiovascular system: pathogenesis and therapeutic targets

Hypoxia,characterized by reduced oxygen concentration,is a significant stressor that affects the survival of aerobic species and plays a prominent role in cardiovascular diseases.From the research history and milestone events related to hypoxia in cardiovascular development and diseases,The"hypoxia-inducible factors(HIFs)switch"can be observed from both temporal and spatial perspectives,encompassing the occurrence and progression of hypoxia(gradual decline in oxygen concentration),the acute and chronic manifestations of hypoxia,and the geographical characteristics of hypoxia(natural selection at high altitudes).Furthermore,hypoxia signaling pathways are associated with natural rhythms,such as diurnal and hibernation processes.In addition to innate factors and natural selection,it has been found that epigenetics,as a postnatal factor,profoundly influences the hypoxic response and progression within the cardiovascular system.Within this intricate process,interactions between different tissues and organs within the cardiovascular system and other systems in the context of hypoxia signaling pathways have been established.Thus,it is the time to summarize and to construct a multi-level regulatory framework of hypoxia signaling and mechanisms in cardiovascular diseases for developing more therapeutic targets and make reasonable advancements in clinical research,including FDA-approved drugs and ongoing clinical trials,to guide future clinical practice in the field of hypoxia signaling in cardiovascular diseases.

Targeting deubiquitinase OTUB1 protects vascular smooth muscle cells in atherosclerosis by modulating PDGFRβ

Atherosclerosis is a chronic artery disease that causes various types of cardiovascular dysfunction.Vascular smooth muscle cells(VSMCs),the main components of atherosclerotic plaque,switch from contractile to synthetic phenotypes during atherogenesis.Ubiquitylation is crucial in regulating VSMC phenotypes in atherosclerosis,and it can be reversely regulated by deubiquitinases.However,the specific effects of deubiquitinases on atherosclerosis have not been thoroughly elucidated.In this study,RNAi screening in human aortic smooth muscle cells was performed to explore the effects of OTU family deubiquitinases,which revealed that silencing OTUB1 inhibited PDGF-BB-stimulated VSMC phenotype switch.Further in vivo studies using Apoe−/−mice revealed that knockdown of OTUB1 in VSMCs alleviated atherosclerosis plaque burden in the advanced stage and led to a stable plaque phenotype.Moreover,VSMC proliferation and migration upon PDGF-BB stimulation could be inhibited by silencing OTUB1 in vitro.Unbiased RNA-sequencing data indicated that knocking down OTUB1 influenced VSMC differentiation,adhesion,and proliferation.Mass spectrometry of ubiquitinated protein confirmed that proteins related to cell growth and migration were differentially ubiquitylated.Mechanistically,we found that OTUB1 recognized the K707 residue ubiquitylation of PDGFRβwith its catalytic triad,thereby reducing the K48-linked ubiquitylation of PDGFRβ.Inhibiting OTUB1 in VSMCs could promote PDGFRβdegradation via the ubiquitin–proteasome pathway,so it was beneficial in preventing VSMCs’phenotype switch.These findings revealed that knocking down OTUB1 ameliorated VSMCs’phenotype switch and atherosclerosis progression,indicating that OTUB1 could be a valuable translational therapeutic target in the future.