Targeting The Local Inflammation In Atherosclerosis Using An Ex-vivo Perfusion System Of Human Coronary Arteries

Atherosclerosis is characterized by the accumulation of lipids, immune cells, and fibrotic tissue in the arterial intima. Although well described as an inflammatory condition, targeting the inflammation component of atherosclerosis while avoiding systemic toxicity remains a clinical challenge. Pro-inflammatory cytokines such as IL-1β and IL-6 have been implicated in atherosclerotic plaque progression and atherothrombotic events. Recent clinical trials have shown promising results targeting these cytokines to reduce the risk of adverse cardiac events in patients, yet systemic toxicity remains a concern. We hypothesize that knocking down the local inflammation using siRNA against IL-1β and/or IL-6 may be a viable therapeutic strategy to treat atherosclerosis. To test our hypothesis, we used an ex-vivo perfusion system of human coronary arteries (hCA) collected from non-transplantable, de-identified hearts ( Fig. A ). Hearts came from donors with or without cardiovascular disease (CVD) risk factors including hypertension, high cholesterol, and diabetes mellitus. hCA isolated from donors with CVD risk factors showed increased IL-1β ( Fig. B ) and IL-6 ( Fig. C ) expression levels assessed by RT-qPCR, compared to controls without risk factors. Perfusion of hCA with media containing TNF-α and IFN-γ increased the expression of both IL-1β and IL-6 ( Fig. D ). Thus, the perfusion system established here will allow us to assess the efficacy of delivering IL-1β and/or IL-6 specific siRNA complexed nanoparticles and will advance the development of novel nanotherapies that target inflammation in atherosclerosis.