Targeting protein phosphatase 2A for takotsubo syndrome treatment

Project Summary/Abstract Takotsubo syndrome (TTS), also known as stress-induced cardiomyopathy or broken heart syndrome, is a condition characterized by sudden temporary ventricle dysfunction secondary to weakening cardiac muscles. Despite considerable research, our current understanding of the underlying pathogenesis and pathophysiology of TTS remains incomplete, thus markedly hindering the development of novel pharmacologic therapies to prevent major adverse cardiovascular events. This proposal describes a research plan that aims to accomplish the following two goals at both the basic science and translational levels: 1) gain deeper understanding of the role of a critical protein phosphatase (protein phosphatase 2A, PP2A) in the pathophysiology of Takotsubo cardiomyopathies; and 2) develop novel small molecule activators of PP2A for the treatment of Takotsubo cardiomyopathies. Reversible protein phosphorylation plays a critical regulatory role in a wide variety of biological processes. The regulation of protein phosphorylation is dictated by the activity of both protein kinases and protein phosphatases. Although there is a significant understanding of how aberrant kinase activity contributes to human cardiovascular disease, the regulation and therapeutic potential of phosphatases in this area remains under- explored. PP2A, a holoenzyme with serine/threonine phosphatase activity, plays a pivotal role in a large array of cellular processes in mammalian cells. Restoration of PP2A activity has been shown to be of significant therapeutic value, however pharmaceutically tractable approaches to directly activate PP2A remain elusive. Our recent observations revealed a marked reduction in PP2A activity in cardiac tissues from isoprenaline-induced TTS mice, as well as in isoprenaline-treated cardiomyocytes. Furthermore, in a murine model of TTS, administration of an orally bioavailable small molecule activator of PP2A, strongly mitigated myocardial damage and improved cardiac function in mice. Additionally, preliminary studies support a role for PP2A in modulating both ferritinophagy and mitophagy in TTS. Collectively, these observations form the basis for the central hypotheses for this grant application: (1) Reduced PP2A activity is involved in the development of acute heart failure in TTS and (2) Reactivation of PP2A may serve as a novel therapeutic strategy to prevent/reverse TTS pathology. Studies in this proposal are designed to extend this new field of cardiac research to gain in-depth understanding of the function of this phosphatase in cardiac biology. The results will greatly enhance our understanding of the molecular and cellular processes involved in the progression of acute heart failure in TTS, potentially paving the way for new therapeutic approaches.