Genetically induced moderate inhibition of 20S proteasomes in cardiomyocytes facilitates heart failure in mice during systolic overload

摘要: Abstract The in vivo function status of the ubiquitin–proteasome system (UPS) pressure overloaded hearts remains undefined. Cardiotoxicity was observed during proteasome inhibitor chemotherapy, especially those with preexisting cardiovascular conditions; however, inhibition (PsmI) also suggested by some experimental studies as a potential therapeutic strategy to curtail cardiac hypertrophy. Here we used genetic approaches probe UPS performance and determine impact cardiomyocyte-restricted PsmI (CR-PsmI) on responses systolic overload. Transgenic mice expressing an inverse reporter (GFPdgn) were subject transverse aortic constriction (TAC) myocardial Mice or without moderate CR-PsmI TAC temporally characterized for severe After (pressure gradient: ~ 40 mm Hg), upregulated first two weeks but turned functional insufficiency between 6 12 weeks evidenced dynamic changes GFPdgn protein levels, peptidase activities, total ubiquitin conjugates. Severe gradients > 60 mm Hg) led within week. Moderate elicited comparable hypertrophic caused malfunction significantly earlier than CR-PsmI. In TAC, inhibited hypertrophy rapidly progressed heart failure premature death, associated pronounced increase cardiomyocyte death. It is concluded that dynamically altered, initial brief upregulation being adaptive; facilitates