Pericardial adipose tissue-derived leptin promotes myocardial apoptosis in high fat diet-induced obese rats through JAK2/ROS/NKA signaling pathway

Abstract

Abstract Background Pathophysiologic mechanisms underlying cardiac structural and functional changes in obesity are complex and linked to adipocytokines released from pericardial adipose tissue (PAT) and cardiomyocyte apoptosis. Although leptin is involved in various pathological conditions, its role in paracrine action of pericardial adipose tissue on myocardial apoptosis remains unknown. Purpose This study was designed to investigate the role of PAT-derived leptin on myocardial apoptosis in high fat diet-induced obese rats. Methods and results Hearts were isolated from lean or high fat diet-induced obese Wistar rats for myocardial remodeling studies. Obese rats had abnormal myocardial structure, diastolic dysfunction, greatly elevated cardiac apoptosis and increased oxidative stress level. Enzyme-linked immunosorbent assay (ELISA) detected significantly higher than circulating leptin level in PAT of obese, but not lean rats. Western blot and immunohistochemical analyses demonstrated increased leptin receptor density in obese heart. H9c2 rat cardiomyoblasts after exposed to PAT-conditioned medium of obese rats exhibited pronounced reactive oxygen species (ROS)-mediated apoptosis, which was partially reversed by leptin antagonist. Moreover, leptin derived from PAT of obese rats inhibited Na+/K+-ATPase activity of H9c2 cells through stimulating ROS, thereby activating calcium-dependent apoptosis. Pretreatment with specific inhibitors revealed that JAK2/STAT3 and PI3K/Akt signaling pathways was involved in the leptin-induced myocardial apoptosis. Conclusion PAT-derived leptin induces myocardial apoptosis in high fat diet-induced obese rats via activating JAK2/STAT3/ROS signaling pathway and inhibiting its downstream Na+/K+-ATPase activity. Funding Acknowledgement Type of funding sources: Foundation. Main funding source(s): Nature Science Foundation of ChinaKey Projects of Shaanxi Science and Technology Research and Development Plan