A single genetic variant in the neuropeptide Y (NPY) pathway may help predict which patients with insulin resistance are at highest risk of heart attacks and strokes. The problem: Neuropeptide Y is known to regulate appetite and metabolism, but its direct effects on human blood vessels and heart tissue are unknown. Researchers have already shown in cardiac surgery patients that the main NPY receptor in human arteries is NPY1R, and that a specific genetic variant (rs16141) is causally linked to insulin resistance, oxidative stress in blood vessels, and altered cardiac event risk. However, no one has yet tested whether NPY directly alters human cardiovascular function. What this research does: The team will apply NPY to human artery and heart tissue samples to measure its effect on superoxide production and endothelial function. They will also map the downstream signalling cascades, particularly how NPY interacts with insulin signalling. Finally, they will test whether NPY-related genetic markers, blood levels, or tissue receptor expression can predict cardiovascular outcomes in patients. Potential impact: If NPY proves to be a direct regulator of vascular oxidative stress, it could become a new therapeutic target or a biomarker for stratifying cardiovascular risk—especially in the large population of patients with insulin resistance who currently lack precise risk prediction tools.
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Background: Neuropeptide Y (NPY) is an endogenous peptide regulating metabolism and satiety. Recent evidence suggests that NPY may be associated with cardiovascular disease. However, the mechanistic effects of NPY on the human cardiovascular system remain unknown. Pilot data: We have used tissue, plasma and genomic data from the Heart, Vessels and Fat cohort (OxHVF, one of the largest translational cohorts of cardiac surgery patients), to interrogate associations of NPY with cardiovascular disease. We have shown that NPY receptor-1 (NPY1R) is the main receptor in human arterial and myocardial samples. We have demonstrated that, in patients with systemic insulin resistance (quantified by established biochemical markers, e.g., HOMA-IR), high NPY1R expression is associated with reduced oxidative stress in human arteries and veins. We have identified several single-nucleotide-polymporphisms in the NPY locus, of which rs16141 is causally linked with systemic insulin resistance, cardiovascular oxidative stress and modification of adverse cardiac event risk. Hypothesis: We hypothesise that NPY directly interacts with cardiovascular insulin signalling, to regulate cardiovascular redox state, particularly in the context of insulin resistance. We further hypothesise that surrogates of NPY signalling such as genomic polymorphisms, circulating NPY levels and cardiovascular NPY1R expression could have predictive value in cardiovascular disease. Aims: Our aims include the characterisation of the direct effects of NPY on cardiovascular sources of superoxide and endothelial function, and description of its downstream signalling cascades, including its interaction with insulin signalling. We further aim to investigate the predictive role of NPY signalling on a range of cardiovascular phenotypes and outcomes.
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