Modulating coronary atherosclerosis through perivascular fat (PVAT)

Summary

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 (i.e., 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) recently 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 and lineage tracing methods and human patient samples, our team will identify if blocking inflammatory signals have any implication 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 -80oC 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 operation time.
Significance: Ultimately, this novel project will uncover biological processes observed in one tissue (e.g., PVAT) may influence processes observed in a different tissue (e.g., blood vessel). In turn, understanding these inter-organ communications will reveal novel pathways with important implications for cardiovascular therapeutics.

Supervisor(s)

Dr Ashish Misra

Research Location

Newtown - Heart Research Institute

Program Type

Masters

Synopsis

Atherosclerosis is an inflammatory arterial disease which involves interplay between immune cells and vascular cells. During the atherosclerotic plaque progression, endothelial cells retention low-density lipids, recruits immune cell into the arterial wall and subsequently activate smooth muscle cells from blood vessel wall. However, recently against the established dogma of this inside-out signaling, perivascular adipose tissue (PVAT) has been proposed as a key regulator of out-side in signaling to regulate atherosclerosis. Herein, we are investigating if under the atherogenic conditions, molecular and cellular signaling related with PVAT modulate atherogenesis. We will be utilizing using state-of-the-art transgenic mice, lineage tracing techniques, human patient samples and molecular biology techniques to identify unique roles of PVAT in atherosclerosis.

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Keywords

inflammation, atherosclerosis, cardiovascular disease, Perivascular adipose tissue, lineage tracing and cellular plasticity

Opportunity ID

The opportunity ID for this research opportunity is: 2913

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