SD COBRE: P21-ACTIVATED KINASE (PAK) SIGNALING IN HYPERTROPHY AND HEART FAILURE

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Doxorubicin (DOX) is a highly effective antitumor agent that can cause heart failure after chronic use in cancer patients. A major theory for DOX cardiac toxicity is the generation of reactive oxygen species (ROS). However, clinical trials have shown very limited effect of antioxidant therapy. The goal of this project is to elucidate novel mechanisms of DOX cardiotoxicity that may be independent of ROS. DOX activates the ubiquitin-proteasome system (UPS) in cardiomyocytes, leading to the degradation of various cardiac proteins. DOX also induces massive autophagy (ATG), a self-digestion mechanism that may cause autophagic cell death if activated inappropriately. We hypothesize that abnormal activation of the UPS and ATG is a novel mechanism of DOX cardiotoxicity, and that inhibition of UPS or ATG will reduce DOX-induced cardiac injury. These hypotheses will be tested by the following specific aims: Aim 1 will determine if blockade of UPS activation by a proteasome inhibitor or small interfering RNA (siRNA)-mediated knockdown of proteasomal subunits can attenuate DOX cardiotoxicity in vitro and in vivo. Aim 2 will test the hypothesis that activation of ATG contributes to DOX cardiotoxicity. We will determine if siRNA knockdown or heterozygous deletion of Beclin1, a gene required for ATG initiation, is able to attenuate DOX cardiotoxicity in vitro and in vivo. Aim 3 will determine if DOX-induced activation of cellular degradation pathways is secondary to oxidative stress. We will determine if reducing ROS production by inactivating NAD(P)H oxidase can block DOX-induced UPS or ATG activity.