Cardiomyocyte Janus kinase 1 (JAK1) signaling is required for cardiac homeostasis and cytokine-dependent activation of STAT3

Abstract

Despite the essential role of inflammation in the pathogenesis of heart failure and other chronic cardiovascular diseases, how cardiomyocytes sense and respond to the inflammatory milieu is not well understood. Cytokine receptors respond to circulating glycoprotein 130 (gp130) family cytokines, such as interleukin-6 (IL-6) and oncostatin M (OSM), by signaling through Janus kinases (JAK) to ultimately elicit phosphorylation-dependent nuclear translocation and transcriptional activity of signal transducer and activator of transcription (STAT) proteins. JAK1 is particularly important for STAT3-dependent cytokine production and macrophage recruitment by cardiomyocytes and STAT3 promotes cardiac hypertrophy and remodeling in response to pressure overload or angiotensin-II but is protective during ischemic injury. However, the roles of JAK1 signaling in cardiac homeostasis and cardiomyocyte cytokine sensing and responsivity remain unclear. To assess the functions of JAK1 in cardiac physiology, we generated mice with cardiomyocyte-specific deletion of JAK1 and evaluated cardiac structure and function, myocardial remodeling, and intracellular signal transduction. Loss of JAK1 in cardiomyocytes results in dilated cardiomyopathy by 6 months of age, indicating cytokine receptor signaling through JAK1 is essential for cardiac physiology. Cardiomyopathy in aged mice lacking cardiomyocyte JAK1 was characterized by substantial myocardial fibrosis. Transcriptomics and gene expression analyses identified JAK1-dependent cytokine-inducible target genes in adult cardiomyocytes as putative effectors of JAK1-STAT3 in the cardiac stress response. JAK1-deficient adult cardiomyocytes were resistant to phosphorylation and nuclear translocation of STAT3 and transcriptional reprogramming in response to OSM. Collectively these data indicate cardiomyocyte JAK1 kinase activity is required for proper cardiac maturation and homeostasis and is indispensable for STAT3 activation and transcriptional responses to OSM.