Increasing evidence links obesity-related health problems, such as insulin resistance, cardiovascular disease and impaired tissue repair, with chronic inflammation. Although dysregulated hematopoietic stem progenitor cell (HSPC) responses are known to be involved, the mechanism(s) underlying obesity-induced dysregulation of inflammation and its downstream impact on healing following ischemia remain unclear. The long-term goal of this study is to understand mechanisms though which obesity and insulin resistance impairs healing after ischemic injury, with a specific focus on epigenetic regulation of HSPCs and dysregulation of inflammation. We hypothesize that obesity and insulin resistance induces HSPC dysregulation that leads to increased supply of inflammatory monocytes, which in turn contributes to prolonged inflammation and impaired healing after ischemic tissue injury. Our preliminary data suggest that this pathway involves mitochondria (mit)-reactive oxygen species (ROS)-induced epigenetic dysregulation in high fat diet (HFD)-induced prediabetic mice. In this study, we propose: (1) To determine the role of prediabetes-induced ROS in histone-3 lysine-4 (H3K4) methylation in HSPCs. We hypothesize that HFD-induced mit-ROS increases H3K4me3 in HSPCs by inducing SET7/9 methyltransferase and inhibiting JARID demethylase activation. (2) To determine the role of prediabetes-induced ROS in HSPC monopoiesis following hindlimb ischemia. We hypothesize that HFD increases inflammatory monopoiesis of HSPCs via mit-ROS-induced H3K4me3. (3) To determine the cell autonomous role of prediabetes-dysregulated HSPCs in tissue recovery following hindlimb ischemia. We hypothesize that prediabetes-dysregulated HSPCs enhance inflammation and impair tissue recovery after hindlimb ischemia in a cell-autonomous and mit-ROS-dependent manner. Our proposed study will begin to elucidate the mechanisms involved in HSPC dysregulation in obesity-related conditions and its impact on inflammatory responses and healing following ischemic injury. If successful, our data will implicate mit-ROS and downstream H3K4 methylation as a key pathway for inducing prediabetes-induced epigenetic memory in HSPCs, and will provide insight into novel therapeutic targets for ischemic cardiovascular diseases in patients with prediabetic pathology.
Obesity and insulin resistance is becoming more common and increases our risk for ischemic vascular disease. The development of obesity- and insulin resistance-related complications is linked to inflammation. Our proposed experiments will determine a novel mechanism by which bone marrow stem cells contribute to persistent inflammation and poor tissue recovery after ischemic event. This study will provide insight into developing novel therapies for ischemic vascular disease in patients with obesity and insulin resistance.
|Fang, Milie M; Barman, Pijus K; Thiruppathi, Muthusamy et al. (2018) Oxidant Signaling Mediated by Nox2 in Neutrophils Promotes Regenerative Myelopoiesis and Tissue Recovery following Ischemic Damage. J Immunol 201:2414-2426|