Vascular Spasm: A Newly Unraveled Cause for Cardiovascular Adversity of Proteasome Inhibition

Abstract

Given the vital role of the ubiquitin-proteasome system (UPS) in result in restrictive cardiomyopathy in pigs (Herrmann et al., 2007; propelling the cell division cycle and sustaining cell survival, UPS inhibition is being intensively explored as a therapeutic strategy for treating malignancy, which is surely fueled by the impressive efficacy demonstrated by proteasome inhibitors bortezomib (BZM) and carfilzomib (CFZ) in treating multiple myeloma (MM) ((Chen-Scarabelli et al., 2017) and references therein). However, severe cardiovascular adverse effects such as sudden death, arrhythmia, angina, heart failure, and pulmonary hypertension to name a few, have been observed in MM patients treated with regimens containing BZM or CFZ ((Enrico et al., 2007, Chen-Scarabelli et al., 2017) and references therein). Most cardiovascular complications are reversible if the use of proteasome inhibitors is timely terminated but prematurely ceasing proteasome inhibitor treatment due to severe unintended effects will obviously limit the clinical benefit of these efficacious agents. Hence, it is extremely important to achieve a better understanding of the underlying causes as it can guide the development of targeted strategies and measures to prevent and manage the life-threatening cardiovascular adverse effects. Prior experimental studies have demonstrated that genetic and pharmacological inhibition of the proteasome in the cardiomyocyte compartment exacerbates acute myocardial ischemia/reperfusion injury and the maladaptive cardiac remodeling andheart failure induced by acute pressure overload (Tang et al., 2010; Tian et al., 2012) through perturbation of protein quality control and exacerbation of proteotoxicity while chronic cardiac proteasome functional insufficiency has been established to play a major role in the genesis and progression of cardiac proteinopathy (Li et al., 2011), pressure overloaded maladaptive cardiac remodeling and failure (Ranek et al., 2015), anddiabetic cardiomyopathy (Li et al., 2017). These prior reports certainly presented a compelling argument for a notion that derangements caused by acute or sustained proteasome inhibition in the cardiomyocyte compartment contribute to at least some of the cardiovascular complications occurred in MM patients receiving proteasome inhibitor-containing chemotherapies. Proteasome malfunction was also implicated in vascular pathology such as atherosclerosis aswell as vascular ageing and pharmacologically induced chronic proteasome inhibition was shown to cause coronary artery constriction, hasten high fat diet induced atherosclerosis, and

DOI: 10.1016/j.ebiom.2017.06.010

Cite this paper

@inproceedings{Wang2017VascularSA, title={Vascular Spasm: A Newly Unraveled Cause for Cardiovascular Adversity of Proteasome Inhibition}, author={Xuejun Wang}, booktitle={EBioMedicine}, year={2017} }