Emerging roles of ubiquitin-specific proteases in the cardiovascular system

The universal posttranslational modification ubiquitination was originally discovered in the 1980s as a tag appended to cellular proteins to mark them for degradation by the 26S proteasomal complex. Subsequent discoveries have established ubiquitination as a process that directs spatial and temporal activities of proteins that are integral to all biochemical pathways in cells, in addition to its canonical role in facilitating life-death decisions of proteins. Protein ubiquitination is counterbalanced by ∼100 enzymes called deubiquitinases (DUBs) expressed in human cells. Although ubiquitination affects a plethora of cellular functions, the role of DUBs was initially linked to neuronal development, and later to cancer, where deregulation of protein degradation coincided with both increased expression of DUBs and worsening of disease pathology. As such, inhibition of DUBs has been regarded as a therapeutic approach for various cancers, and major investments of time and resources have been dedicated for developing DUB inhibitors for cancer therapy. The important roles of DUBs in the cardiovascular system have only recently been appreciated. DUBs play a protective anti-inflammatory role in the vascular smooth muscle, endothelium, as well as macrophages, and also serve to mitigate pathological remodeling of the myocardium in mice. Activation or positive allosteric modulation of DUBs could provide therapeutic benefit in the 2 major cardiovascular diseases, atherosclerosis and heart failure. In this review, we highlight the roles of select DUBs that have been characterized for their critical functions in the heart and vasculature. SIGNIFICANCE STATEMENT: Cardiovascular diseases represent a major global health burden and remain the leading cause of morbidity and mortality, accounting for approximately 18 million deaths annually worldwide. Among these, atherosclerosis and heart failure are 2 interrelated conditions with multifactorial, chronic, and complex etiologies, necessitating the development of more effective therapeutic strategies to reduce mortality and improve quality of life. Emerging evidence suggests that several deubiquitinases exert protective effects by attenuating atherosclerosis and cardiac dysfunction in murine models, highlighting the potential of deubiquitinase modulators to serve as novel therapeutic agents for cardiovascular diseases.