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September 5th, 2025
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Norwegian University of Science and Technology (NTNU), Faculty of Medicine and Health/ Department of Circulation and Medical Imaging, Trondheim, Norway
molecular biology
bioRxiv

Pivotal role of Disrupted-in-Schizophrenia 1 (DISC1) in cardiac resilience to ischemic stress

Gurdeep Marwahra, G.Open in Google Scholar•Pinho, M. J.Open in Google Scholar•Scrimgeour, N. R.Open in Google Scholar•Slagsvold, K. H.Open in Google Scholar•Wahba, A.Open in Google Scholar•Rosbjorgen, R. E.Open in Google Scholar•Enguita, F. J.Open in Google Scholar•Yang, K.Open in Google Scholar•Ishizuka, K.Open in Google Scholar•Casas, C. A. A.Open in Google Scholaret al.

Molecular targets that contribute to post-myocardial infarction heart failure remains elusive. Here we studied the global transcriptional landscape of human inducible pluripotent stem cell-derived cardiomyocytes under simulated ischemia at the whole genome level in an unbiased manner. Unexpectedly, we identified Disrupted in Schizophrenia 1 (DISC1), which has been almost exlusively studied in neurodevelopment/neurosignaling, as a key molecule. Reduced DISC1 levels increase infarct size in mouse hearts, increases cTnT release following surgery in coronary artery bypass grafting patients and decrease the survival of human AC16 cardiomyocytes exposed to ischemic conditions by disrupting cardioprotective pathways. Mechanistically, the loss of DISC1 interaction with Glycogen Synthase Kinase 3 Beta (GSK3{beta}) heightens GSK3{beta} activity, promoting cell death. Conversely, increasing DISC1 levels enhances cardioprotective signaling by maintaining the DISC1-GSK3{beta} interaction. Although DISC1 is known to interact with many proteins as an intracellular hub, we have identified that its specific interaction with GSK3{beta} is crucial for cardioprotection. These data also indicate that a key molecule involved in brain health and disease also contributes to cardiac health and disease, supporting the idea that neuropsychiatric conditions are systemic.

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