Abstract
<jats:p>Background: Takotsubo syndrome (TTS) is an acute stress-induced cardiomyopathy characterized by transient left ventricular dysfunction. Despite its reversible nature, TTS is associated with substantial morbidity and mortality in the acute phase, and no specific treatments are available. The precise molecular mechanisms that connect catecholamine stress to reversible myocardial injury are not fully understood. PP2A, a holoenzyme with serine/threonine phosphatase activity, plays a vital role in normal cardiac development, and its dysregulation has been associated with heart disease. Its role in TTS and its potential as a therapeutic target remain completely unknown. Methods: Analysis of public multi-omics datasets from stress cardiomyopathy (SCM) and experimental models of TTS, along with treatment of cardiomyocytes with human TTS plasma, was used to investigate a potential role for protein phosphatase 2A (PP2A) in stress-induced myocardial injury. To clarify the functional impact of manipulating PP2A activity in TTS, we used a series of disease relevant cell based and in vivo models, leveraging both genetic and pharmacological approaches to modulate PP2A activity in cardiomyocytes and in mice. To gain mechanistic insights into how PP2A influences TTS pathology and downstream signaling pathways, RNA sequencing, stress-responsive iron handling, mitochondrial function, and cardiac phenotypes were thoroughly evaluated in both in vivo and in vitro studies. Results: PP2A activity was markedly reduced in cardiac tissues from mice with isoprenaline-induced TTS, as well as in isoprenaline-treated cardiomyocytes. Genetic or pharmacological inhibition of PP2A worsened catecholamine-induced cardiac dysfunction and myocardial injury. Most notably, pharmacological activation of PP2A using an orally bioavailable small-molecule activator strongly mitigated myocardial damage and enhanced cardiac function in TTS models. Mechanistically, PP2A inactivation promoted JNK-MAPK signaling and dysregulated stress-responsive iron-handling pathways, leading to ferritinophagy-mediated ferroptosis and mitochondrial dysfunction. Pharmacological JNK inhibition effectively rescued myocardial injury caused by PP2A deficiency in two TTS animal models and in cardiomyocytes. Conclusions: PP2A inactivation is a key molecular event linking catecholamine stress to myocardial injury in TTS. Restoring PP2A activity or inhibiting downstream JNK attenuates ferritinophagy-dependent stress responses and mitochondrial dysfunction, providing a unifying mechanistic framework and highlighting the PP2A-JNK axis as a potential target for short-term intervention during the acute phase of TTS.</jats:p>