Abstract Body: BACKGROUND: Disruption of iron homeostasis is widely recognized as a key contributor to the pathogenesis of cardiomyopathy and heart failure. Protein phosphatase 2A (PP2A), a crucial serine/threonine phosphatase, has recently gained an increased appreciation due to its functional importance in cardiovascular biology. However, a complete understanding of PP2A function in the pathology of takotsubo syndrome (TTS) is lacking.
OBJECTIVE: To characterize the functional role of PP2A in the regulation of cardiac iron homeostasis and TTS progression.
METHODS: Using a single high-dose injection of isoprenaline (ISO; 400 mg/kg) in a TTS-like mouse model, gain- and loss-of-function studies were performed to understand the role of PP2A in TTS. In addition, in vitro studies in H9C2 cardiomyocytes and primary human cardiac myocytes were conducted to study the underlying molecular mechanisms by which PP2A impacts TTS.
RESULTS: In murine TTS, a profound decrease of PP2A activity in cardiomyocytes (as indicated by diminished methylation of the PP2A catalytic subunit) was observed. This was accompanied by molecular features typical of ferroptosis, including increased cardiac iron levels and increased lipid peroxidation. Furthermore, myocardial-specific knockout of PP2A in mice exacerbated ferritinophagy, resulting in the accumulation of labile iron and further disrupted mitochondrial homeostasis, thereby aggravating cardiomyocyte ferroptosis. Conversely, administration of the lead small molecule activator of PP2A (SMAP), DT-061, increased methylation of the PP2A catalytic subunit, inhibited cardiomyocyte ferroptosis, alleviated acute cardiac injury, and prevented TTS progression.
CONCLUSIONS: These results demonstrate that PP2A plays a critical role in protecting against cardiac ferroptosis and acute heart failure, thereby providing a novel therapeutic target for the prevention and treatment of TTS.