Loss of the protein disrupted in schizophrenia 1 (DISC1) impairs cardiac resistance against ischemia

Abstract

AbstractTreatable targets that hinder heart failure development following myocardial infarction remain limited. Through an unbiased transcriptional regulation study for ischemic heart disease, we identified the protein disrupted in schizophrenia 1 (DISC1), which has been almost solely characterized in the brain. Here, we show that loss of DISC1 is a major driver of heart disease and ischemic damage. Silencing of DISC1 sensitizes human cardiomyocyte cell lines to hypoxia, whereas DISC1 overexpression is cardioprotective. Mechanistically, we provide evidence that reduced DISC1 protein levels interrupt multiple signaling processes vital for cardiomyocyte survival whereas overexpression of DISC1 enhances pro survival signalling. The present study has implications for understanding scenarios where cardiomyocytes are unable to increase the levels of DISC1 during ischemia, e.g., in individuals with DISC1 genetic defects. Indeed, patients with severe mental illness display 20 years earlier mortality, with IHD as the greatest cause of death. The present study can thus shed light on this long-term enigma in epidemiology. Furthermore, the promising data showing activation of pro survival signalling processes with DISC1 overexpression opens new directions towards potential treatment strategies of patients suffering from ischemic heart disease.