Abstract Body (Do not enter title and authors here): Background: 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.
Hypothesis: Reduced Protein phosphatase 2A (PP2A) activity is involved in the development of acute heart failure in TTS, and reactivation of PP2A may serve as a novel pharmacological therapy for the treatment of TTS.
Methods: To investigate the clinical relevance of PP2A in TTS, serum from acute-phase TTS patients was used to treat H9C2 cardiomyocytes and primary human cardiac myocytes for 2 hours. Moreover, a TTS-like mouse model was established by a single high-dose injection of isoprenaline (ISO; 400 mg/kg), and both gain- and loss-of-function strategies were used to assess the in vivo role of PP2A. In addition, mechanistic studies were conducted in vivo and in vitro to elucidate how PP2A modulates TTS pathophysiology.
Results: Treatment of H9C2 cardiomyocytes and primary human cardiomyocytes with serum from TTS patients resulted in a significant reduction in PP2A activity. Consistent reductions in PP2A activity were observed in cardiac tissues from ISO-induced TTS mice, as well as in ISO-treated cardiomyocytes. Furthermore, administration of an orally bioavailable small molecule activator of PP2A, DT-061, strongly mitigated myocardial damage and improved cardiac function in TTS mice. Additionally, mechanistic studies in both in vivo and in vitro models supported a role for PP2A in modulating ferroptosis-mediated ferritinophagy in TTS. Conversely, treatment with the PP2A inhibitor LB-100 or cardiomyocyte-specific knockdown of PP2A-C in TTS mice led to exacerbated cardiac dysfunction and enhanced ferritinophagy activation.
Conclusions: These results demonstrate that PP2A plays a critical role in protecting against cardiac ferroptosis and acute heart failure, thereby providing a novel pharmacological therapy for the prevention and treatment of TTS.