Comparative analysis of isoproterenol- and lipopolysaccharide-mediated cytoprotective responses in the heart

A panoply of different stimuli activates endogenous signaling pathways that confer cardioprotection in the heart; however, it is unclear whether these stimuli engage similar or distinct biological pathways. We showed that tissue injury induced by isoproterenol (ISO), or pretreatment with the Toll-like receptor 4 agonist lipopolysaccharide (LPS), protects the heart against the myopathic effects of a subsequent exposure to ISO. Here, we used a multiomic approach to examine ISO- and LPS-treated hearts to identify shared and distinct biological themes. Bulk RNA sequencing showed that ISO and LPS elicited upregulation of distinct stress response signatures that featured interferon (IFN) signaling, while converging on the widespread downregulation of pathways related to metabolism or cell growth. Multiome (RNA + ATAC) sequencing revealed that ISO-treated hearts underwent distinct chromatin remodeling, with more regions showing decreased accessibility than increased accessibility. IFN-related pathways were consistently enriched across many cell types in the heart, including endocardial cells, TNK cells, myeloid cells, and endothelial cells. Analysis of cell-cell interactions using CellChat showed that ISO stimulation enhanced communication between myeloid cells with fibroblasts, TNK cells, and pericytes. Remarkably, cell-cell interactions for cardiac myocytes were restricted to myeloid cells. Bulk ATAC sequencing of bone marrow-derived hematopoietic stem and progenitor cells (HSPCs) demonstrated that ISO and LPS stimulation predominantly resulted in decreased chromatin accessibility in HSPCs and bone marrow stromal cells. Viewed together, these studies show that although ISO and LPS engage distinct upstream signaling pathways, both converge on IFN signaling and a shared suppression of energy-intensive pathways.NEW & NOTEWORTHY This study shows that isoproterenol and lipopolysaccharide establish cardioprotection through the activation of distinct upstream signaling and cell-cell communication networks that converge on interferon signaling in the heart. Viewed together, these studies suggest an important role for immune-mediated cardioprotection as a mechanism for enhancing cardiac resilience in response to stress.