Among patients with unstable angina or myocardial infarction without ST-segment elevation, prasugrel did not significantly reduce the frequency of the primary end point, as compared with clopidogrel, and similar risks of bleeding were observed. (Funded by Eli Lilly and Daiichi Sankyo; TRILOGY ACS ClinicalTrials.gov number, NCT00699998.).
Sawaya SE, Rajawat YS, Rami TG, Szalai G, Price RL, Sivasubramanian N, Mann DL, Khoury DS. Downregulation of connexin40 and increased prevalence of atrial arrhythmias in transgenic mice with cardiac-restricted overexpression of tumor necrosis factor.
Background
Sustained inflammation in the heart is sufficient to provoke left ventricular (LV) dysfunction and LV remodeling. Although inflammation has been linked to many of the biologic changes responsible for adverse LV remodeling, the relationship between inflammation and protein quality control in the heart is not well understood.
Methods and Results
To study the relationship between chronic inflammation and protein quality control we utilized a mouse model of dilated cardiomyopathy driven by cardiac restricted overexpression of TNF (Myh6-sTNF). Myh6-sTNF mice develop protein aggregates containing ubiquitin tagged proteins within cardiac myocytes related to proteasome dysfunction and impaired autophagy. The 26S proteasome was dysfunctional despite normal function of the core 20S subunit. We found an accumulation of autophagy substrates in Myh6-sTNF mice, which was also seen in tissue from patients with end stage heart failure. Moreover, there was evidence of impaired autophagosome clearance following chloroquine administration in these mice indicative of impaired autophagic flux. Finally, there was increased mTORC1 activation, which has been linked to inhibition of both the proteasome and autophagy.
Conclusion
Myh6-sTNF mice with sustained inflammatory signaling develop proteasome dysfunction and impaired autophagic flux that is associated with enhanced mTORC1 activation.
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