Proteasome inhibition ablates activation of NF-κB in myocardial reperfusion and reduces reperfusion injury

Abstract

Both acute coronary occlusion and reperfusion of an infarct-related artery lead to significant myocardial cell death. Recent evidence has been presented that activation of the transcription factor nuclear factor-κB (NF-κB) plays a critical role in reperfusion injury. NF-κB is usually bound to its inhibitor, IκB, and classic activation of NF-κB occurs when the 20S proteasome degrades IκB that has been phosphorylated and ubiquitinated. In this study, activation of NF-κB was inhibited by systemic administration of a 20S proteasome inhibitor (PS-519) in a porcine model of myocardial reperfusion injury. The experimental protocol induced myocardial ischemia in the distribution of the left anterior descending coronary artery for 1 h with subsequent reperfusion for 3 h. A single systemic treatment with PS-519 reduced 20S proteasome activity; blocked activation of NF-κB induced by reperfusion; reduced creatine kinase, creatine kinase-muscle-brain fraction, and troponin I release from the myocardium; preserved regional myocardial function measured by segmental shortening; significantly reduced the size of myocardial infarction; and exhibited no acute toxicity. These data show that myocardial reperfusion injury can be inhibited by using proteasome inhibitors, which likely function through the inhibition of NF-κB activation.

Sanggenon C decreases tumor cell viability associated with proteasome inhibition

“…LDH release as shown in (E), and cell death assay by flow cytometry was shown in (F) and (G). Table 1 1 H (500 MHz) and 13 C (125 MHz) NMR spectral data (DMSO-d 6 ) for Sanggenon C …”

“…Proteasome inhibition has been demonstrated as a novel therapeutic strategy in multiple disease models, including fibrosis (4), inflammation (5), ischemia-reperefusion injury (6), myocardial hypertrophy (7) and cancer (8). Proteasome inhibitor bortezomib (Valcade or PS-341) has been approved by the United States FDA to treat multiple myeloma.…”

Understanding Proteasome Assembly and Regulation: Importance to Cardiovascular Medicine

“…The relationship between oxidized or ubiquitinated proteins and the proteasome directly correlate with postischemic recovery (Powell et al 2005), while some cardioprotective proteins are stimulated during proteasome inhibition (Stangl et al 2002, Townsend et al 2004. Proteasome inhibitors during I/R injury have also been found to decrease myocardial infarct size, reduce leukocyte accumulation and almost entirely eliminate coronary contractile dysfunction (Pye et al 2003, Campbell et al 1999. Collectively, multiple lines of evidence documented a relationship of altered proteasome function in diseased myocardium.…”

“…Of particular interest are the perturbations in proteasome activities associated with cardiovascular disease phenotypes. Despite several controversial reports, there is an emerging consensus that injured myocardium (e.g., myocardial ischemia reperfusion injury, left ventricular dysfunction) is concomitant with an attenuated proteolytic function in the heart (Bulteau et al 2001, Gurusamy et al 2007, Voortman and Giaccone 2006, Luss et al 2002, Pye et al 2003, Stansfield et al 2007.…”

Explore the murine cardiac 20S proteasomes : molecular composition and regulation.

“…Nevertheless, several hypotheses nave been proposed. (Campbell, Adams et al 1999;Elliott, Zollner et al 2003;Pye, Ardeshirpour et al 2003). …”