Role of redox-activated CaMKII delta and PKA RIalpha in doxorubicine-induced cardiomyopathy

• Applicant: Professor Dr. Can Martin Sag
• Subject Area: Cardiology, Angiology
• Term: since 2016
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 325253330

Anthracyclines such as doxorubicin (DOX) are clinically used as first-line therapy for the treatment of high-prevalence cancers such as breast carcinoma. Patients treated curatively nowadays have a good oncological prognosis, which, however, can be dramatically limited by the occurrence of doxorubicin-induced cardiomyopathy (DICM). For example, approximately 9% of all breast cancer patients experience clinically manifest heart failure within the first year after initiation of DOX therapy. The underlying pathomechanisms of DICM are poorly understood, and no established therapeutic strategies exist clinically. However, from studies using cellular and animal models of DICM, it is known that DOX causes a dramatic increase in toxic reactive oxygen species (ROS) in cardiomyocytes. The consequence is redox-induced damage to intracellular calcium metabolism with contractile dysfunction of the cardiac myocyte/DICM. However, therapeutic use of radical scavengers to treat DICM would attenuate the antitumor effect of doxorubicin in tumor tissue, which is based on an antitumor effect of ROS. In addition, the partially physiological functions of redox-dependent protein kinases in intracellular calcium metabolism would also be negatively affected. Based on my previous work on the importance of redox-activated Ca2+/calmodulin-dependent protein kinase II delta (CaMKII delta) and redox-activated protein kinase A RI alpha (PKA RIalpha) for intracellular calcium metabolism in the heart, I would like to investigate the pathophysiological significance of these redox-dependent protein kinases for the development of DICM in the context of the proposed follow-up research project. Furthermore, I would like to evaluate specific therapeutic options for DICM by differential modulation of CaMKII delta and/or PKA RIalpha activity. Thus, on the one hand, I expect an enhancement of DICM by a pathological oxCaMKII delta-related calcium leak from the sarcoplasmic reticulum, which should be attenuated in a "redox-dead" CaMKII delta mouse model. In contrast, I expect DICM to be attenuated by compensatory oxPKARI alpha-related stimulation of L-type calcium channel-mediated transsarcolemmal calcium influx (ICa), which should be absent in a redox-dead PKARI alpha mouse model.

• DFG Programme: Research Grants