Association of Circulating Robo4 with Obesity, Hypertension and Atherosclerotic Plaque Burden

Atherosclerotic cardiovascular disease (ASCVD) remains the leading cause of death worldwide. Type 2 diabetes mellitus (T2DM) is a major risk factor for ASCVD development, being associated with endothelial dysfunction and accelerated atherosclerosis. In the current study we aimed to explore the potential value of circulating Robo4 (soluble Robo4, sRobo4), an endothelial-specific receptor that regulates endothelial cell (EC) junctional integrity, vascular permeability, EC-mediated inflammatory responses and angiogenesis, as a marker of vascular disease in individuals with or without T2DM. Thirty-four individuals with T2DM and 15 non-diabetic individuals (control) of similar age and sex were included in the study. sROBO4 was comparable between individuals with T2DM and control (T2DM: 1.54±1.19 vs control: 1.59±0.77 ng/mL, P=0.46). Of interest, sRobo4 positively correlated with body mass index (BMI) (rs=0.384, P=0.006), and negatively correlated with renal function as determined by estimated glomerular filtration rate (rs= -0.429, P=0.003). Moreover, individuals with arterial hypertension had higher sRobo4 compared to normotensive individuals (P=0.03). More importantly, we observed that individuals with 2 or more atherosclerotic plaques (n=28) in their femoral and/or carotid arteries had significantly higher sRobo4 levels compared to individuals with a total of none or 1 atherosclerotic plaque (n=20) (P=0.008). The association of sRobo4 with higher atherosclerotic burden remained significant when separately controlling for the effect of age, sex, presence of T2DM, total cholesterol, or BMI levels. In vivo studies utilizing models of atherosclerosis as well as larger prospective cohort studies are warranted to delineate causality and prognostic value of sRobo4 in atherosclerotic cardiovascular disease.