Multi‐Omic Approach to Identifying Altered Metabolic and Signaling Pathways in the Mouse Heart with Chronic Exposure to Atypical Antipsychotic Medications

Abstract

Atypical (AA) antipsychotic drugs, including Risperidone (RIS) and Olanzapine (OLAN), cause cardiac arrhythmia and significant endocrine and metabolic risk factors for cardiovascular disease, including obesity, insulin resistance, hyperglycemia, and dyslipidemia. AA drugs have complex pharmacology, antagonizing G‐protein coupled receptors including: dopamine, serotonin, α‐adrenergic and muscarinic receptors. However, the underlying pharmacology linking cardiovascular morbidities to AA therapy is unknown. We hypothesize that AAs may alter cardiac energy metabolism and present early gene expression markers in the pathogenesis to cardiovascular disease. In this study we aim to investigate the mechanisms by which AAs may promote cardiometabolic dysfunction. Male B6 mice were dosed daily with either 5 mg/kg OLAN or 1 mg/kg RIS or vehicle control (V) for 4 weeks and chronic effects of AAs were assessed in whole heart ventricles by RNAseq, miRNAseq and Proteomic analysis. Results suggest changes in transcriptomic and proteomic profiles and in the mouse heart with chronic exposure to AAs relating to mitochondrial dysfunction, lipid oxidation and metabolism, contractility, cardiac hypertrophy and PPAR signaling. Further pathway analysis of these data sets using Ingenuity Pathway Analysis revealed altered canonical pathways and disease and function that are consistent between the RIS and OLAN treated groups compared to V. To further investigate the effect of AA treatment on cardiac mitochondrial function, cardiac mitochondria were isolated from female B6 mice dosed 4 weeks daily with V or 0.75 mg/kg RIS and oxygen consumption studies were performed on the XF24 extracellular flux analyzer (Agilent) to measure various respiratory states. Isolated mitochondria were well coupled and showed a RCR (OCRADP/OCROligo) of ~ 3. RIS treatment led to an increase in State II (Succinate) and State III (phosphorylating) respiration compared to V. In conclusion, our data demonstrate chronic effects of AAs on cardiac mitochondrial function and bioenergetics and indicators of cardiac function.Support or Funding InformationThis work was funded in part by NIH grant DK095413 awarded to KH and NIH grant AR067858 awarded to KJM.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.