Endothelial Cell Stimulator of Interferon Genes Regulates IL-6 Production and Is Required for Pathologic Cardiac Hypertrophy and Contractile Dysfunction in Experimental Heart Failure
Erin Sanders , Kuljeet Kaur , Noah Wagner , Ramona Emig , Mark Aronovitz , Abraham L. Bayer , Brandon Theall , Albert Tai , Nina Martino , Miranda E. Good , Alejandro P. Adam , Robert Blanton , Pilar Alcaide
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引用次数: 0
Abstract
Capillary rarefaction and cardiomyocyte (CM) hypertrophy are hallmarks of the complex syndrome of heart failure (HF), a leading cause of hospitalization and death. Molecular signals within and between cellular components of the heart have emerged as central hubs that modulate cardiac pathophysiology. The stimulator of interferon genes (STING) was highly expressed in human and mouse cardiac endothelial cells (ECs) and was activated at the onset of HF. Global and inducible EC-specific STING−/− mice were used to demonstrate that EC STING is required for contractile dysfunction in an experimental model of HF induced by transverse aortic constriction, through the regulation of CM hypertrophy and capillary rarefaction. ECs from EC-STING−/− mice subjected to transverse aortic constriction were enriched in gene sets related to integrin and cell adhesion to extracellular matrix compared with controls. CellChat analysis of human cardiac cells from patients with nonischemic cardiomyopathy revealed EC-CM communication, and mechanistically, STING activation induced IL-6 secretion. Furthermore, EC-derived IL-6 was necessary to induce prohypertrophic gene expression in CMs in a STING-dependent manner. The study demonstrates a novel role for STING in ECs, contributing to hypertrophy and contractile dysfunction in experimental HF.
期刊介绍:
The American Journal of Pathology, official journal of the American Society for Investigative Pathology, published by Elsevier, Inc., seeks high-quality original research reports, reviews, and commentaries related to the molecular and cellular basis of disease. The editors will consider basic, translational, and clinical investigations that directly address mechanisms of pathogenesis or provide a foundation for future mechanistic inquiries. Examples of such foundational investigations include data mining, identification of biomarkers, molecular pathology, and discovery research. Foundational studies that incorporate deep learning and artificial intelligence are also welcome. High priority is given to studies of human disease and relevant experimental models using molecular, cellular, and organismal approaches.