Background: Organ-to-organ communications are vital for living systems and play critical roles in cellular homeostasis. Various studies have demonstrated the existence and significance of evolutionally conserved factors involved in inter-organ communication. Hindrance in this intricate network of inter-organ communication initiates development of disease (eg cancer, obesity, aging and vascular disorders). Perivascular adipose tissue (PVAT) anatomically proximal to vasculature has a distinctive cellular composition that modulates a range of cardiovascular disease (CVD) processes. Recently, it was shown that PVAT and the vessel wall communicate bidirectionally through release of inflammatory molecules, adipokines and oxidative products; as such, PVAT may be a potential therapeutic target in cardiovascular disease.
Rationale: Antonopolous et al (Science Translational Medicine, 2017) showed that inflammatory signals from the human arterial wall diffuse into the perivascular fat to influence adipocyte lipid content. We have previously shown that low dose colchicine therapy in patients with coronary disease significantly reduced inflammatory trans-coronary cytokine levels (Martinez et al, Journal of the American Heart Association, 2015). As such, we hypothesise that colchicine pre-treatment prior to cardiac surgery will reduce diffusion of inflammatory cytokines from the vessel wall, thereby inhibiting differentiation of pre-adipocytes into mature adipocytes. Using novel transgenic mouse model, lineage tracing methods and human patient samples, our team will identify what implication blocking inflammatory signals has on progression of atherosclerosis.
Experiment plan: We will study atheroprone mice carrying a fluorescent reporter (GFP) in macrophages to determine effects of colchicine on macrophage proliferation, macrophage fate change (from M1 to M2), and their migration from the adventitial layer to the perivascular fat. We will further investigate whether colchicine can modulate established plaque through inhibiting differentiation of pre-adipocytes into mature adipocytes and reducing adipocyte inflammation. We will confirm these findings on human patient samples. 40 consecutive patients enrolled in the COLPOC study will undergo adipose tissue harvesting from the following sites: chest incision (EpAT) (control), central thoracic area attached to the pericardium (ThAT), and right atrioventricular groove (ScAT), away from visible vessels. Samples will be snap frozen immediately after harvesting and stored at -80C for histology and gene expression studies. In detail, adipocyte size and adipocytes per field will be quantified from tissue sections of EpAT, ThAT, and ScAT from the same patients. Gene expression for FABP4, PPAR-g, CEBPA and FABP4 (key adipocyte differentiation markers) will also be assessed. Fat sampling will incur no additional risk to the patient or increase in surgery time.
Significance: Ultimately, this novel project will uncover how biological processes observed in one tissue (e.g., PVAT) may influence key processes observed in a different tissue (e.g., blood vessel). In turn, understanding these inter-organ communications will increase our understanding of pathways in cardiovascular disease, hence provide new avenues to explore with existing and new therapeutics.