High density lipoprotein modulates osteocalcin expression in circulating monocytes: a potential protective mechanism for cardiovascular disease in type 1 diabetes

Ernesto Maddaloni,Stephanie D’Eon,Kyoungmin Park,George L King,Ronald St-Louis,Hillary A Keenan,Yu Xia,Liane J Tinsley,Qian Li,Mogher Khamaisi

doi:10.1186/s12933-017-0599-2

Ernesto Maddaloni, Stephanie D’Eon + Show 8 more

Open Access

https://doi.org/10.1186/s12933-017-0599-2

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Abstract

BackgroundCardiovascular disease (CVD) is a major cause of mortality in type 1 diabetes (T1D). A pro-calcific drift of circulating monocytes has been linked to vascular calcification and is marked by the surface expression of osteocalcin (OCN). We studied OCN+ monocytes in a unique population with ≥50 years of T1D, the 50-Year Joslin Medalists (J50M).MethodsCD45 bright/CD14+/OCN+ cells in the circulating mononuclear blood cell fraction were quantified by flow cytometry and reported as percentage of CD45 bright cells. Mechanisms were studied by inducing OCN expression in human monocytes in vitro.ResultsSubjects without history of CVD (n = 16) showed lower levels of OCN+ monocytes than subjects with CVD (n = 14) (13.1 ± 8.4% vs 19.9 ± 6.4%, p = 0.02). OCN+ monocytes level was inversely related to total high density lipoprotein (HDL) cholesterol levels (r = −0.424, p = 0.02), large (r = −0.413, p = 0.02) and intermediate (r = −0.445, p = 0.01) HDL sub-fractions, but not to small HDL. In vitro, incubation with OxLDL significantly increased the number of OCN+ monocytes (p < 0.01). This action of OxLDL was significantly reduced by the addition of HDL in a concentration dependent manner (p < 0.001). Inhibition of the scavenger receptor B1 reduced the effects of both OxLDL and HDL (p < 0.05).ConclusionsLow OCN+ monocytes levels are associated with lack of CVD in people with long duration T1D. A possible mechanism for the increased OCN+ monocytes could be the elevated levels of oxidized lipids due to diabetes which may be inhibited by HDL. These findings suggest that circulating OCN+ monocytes could be a marker for vascular disease in diabetic patients and possibly modified by HDL elevation.

Highlights

Cardiovascular disease (CVD) is a major cause of mortality in type 1 diabetes (T1D)
Our studies extend the association of osteoc‐ alcin (OCN)+ monocytes and CVD in T1D which while having similarities with type 2 diabetes (T2D) differs in that individuals with T1D develop CVD often without the typical insulin resistance hallmarks seen in T2D [15]
In conclusion, this study supports an association between CVD protection and lower levels of circulating osteogenic cells of myeloid origin in long duration T1D, along with higher high density lipoprotein (HDL)-c levels, those of larger sub-particle size

Summary

Introduction

A pro-calcific drift of circulating monocytes has been linked to vascular calcification and is marked by the surface expression of osteoc‐ alcin (OCN). On the other hand, circulating osteoprogenitor cells, defined as circulating cells co-expressing osteocalcin (OCN) together with the progenitor stem cell antigen CD34, have been found increased in subjects with cardiovascular disease with and without diabetes [7]. Because of their pro-calcific phenotype, these cells are hypothesized to contribute to the development of vascular calcification and atherosclerosis [8]. Growing evidence demonstrates the ability of circulating OCN+ mononuclear cells to contribute to ectopic ossification [12,13,14]

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