Impaired peroxisomal import in Drosophila hepatocyte-like cells induces cardiac dysfunction through the pro-inflammatory cytokine Upd3

Abstract

27Age is a major risk factor for cardiovascular diseases. Currently, the non-autonomous 28 regulation of age-related cardiac dysfunction is poorly understood. In the present study, we 29 discover that age-dependent induction of cytokine unpaired 3 (Upd3) in Drosophila oenocytes 30(hepatocyte-like cells), due to a dampened peroxisomal import function, is the primary non-31 autonomous mechanism for elevated arrhythmicity in old hearts. We show that Upd3 is 32 significantly up-regulated (52-fold) in aged oenocytes. Oenocyte-specific knockdown of Upd3 is 33 sufficient to block aging-induced cardiac arrhythmia. We further show that the age-dependent 34 induction of Upd3 is triggered by impaired peroxisomal import and elevated JNK signaling in 35 aged oenocytes. Intriguingly, oenocyte-specific over-expression of Pex5, the key peroxisomal 36 import receptor, restores peroxisomal import, blocks age-related Upd3 induction, and alleviates 37 aging-and paraquat-induced cardiac arrhythmicity. Thus, our studies identify an important role 38 of the evolutionarily conserved pro-inflammatory cytokine signaling and hepatocyte-specific 39 peroxisomal import in mediating non-autonomous regulation of cardiac aging. 41Age is a major risk factor for a wide range of human diseases 1 . For example, aging is 54 associated with a great increase in the incidence of cardiovascular diseases (CVD), one of the 55 leading causes of death worldwide 2, 3 . During aging, cardiomyocytes undergo rapid remodeling 56 with a variety of intracellular changes, in particular impaired mitochondrial quality control, 57 increased production of reactive oxygen species (ROS), and elevated inflammation 1 . The chronic 58 and systemic inflammation (or "inflammaging") is often associated with increased levels of 59 circulating pro-inflammatory biomarkers (e.g., interleukin-6/IL-6 and C-reactive protein/CRP), 60 which are notable risk factors for cardiovascular diseases 4, 5 . The cause of inflammaging and its 61 impact on cardiac aging are still poorly understood. It is known that short-term expression of 62 inflammatory cytokines (e.g., IL-6) can protect myocytes from injury-induced apoptosis. However, 63prolonged production of IL-6 induces pathological hypertrophy and decreases cardiomyocyte 64 contractility through the activation of Janus Kinases-Signal Transducer and Activator of 65 Transcription (JAK-STAT) signaling 6 . Elevated levels of circulating IL-6 are often associated with 66 heart failure, myocardial damage and atherosclerosis 6-8 . IL-6 can be produced not only by 67 cardiomyocytes themselves in response to ischemia-reperfusion injury and myocardial infarction, 68 but also by other neighboring tissues (e.g., endothelial cells and vascular smooth-muscle), 69 immune cells (e.g., monocytes and macrophages), as well as liver 7, 9 . However, the root causes 70 of inflammaging and the primary sources of these inflammatory factors remain to be determined. 71Liver is a major endocrine organ that produces a wide variety of systemic factors to 72 coordinate ...