Insulin and IGF1 receptors in human cardiac microvascular endothelial cells: metabolic, mitogenic and anti-inflammatory effects

Abstract

Diabetes is associated with microcirculatory dysfunction and heart failure and changes in insulin and IGF1 levels. Whether human cardiac microvascular endothelial cells (HMVEC-Cs) are sensitive to insulin and/or IGF1 is not known. We studied the role of insulin receptors (IRs) and IGF1 receptors (IGF1Rs) in metabolic, mitogenic and antiinflammatory responses to insulin and IGF1 in HMVEC-Cs and human umbilical vein endothelial cells (HUVECs). IR and IGF1R gene expression was studied using real-time RT-PCR. Receptor protein expression and phosphorylation were determined by western blot and ELISA. Metabolic and mitogenic effects were measured as glucose accumulation and thymidine incorporation. An E-selectin ELISA was used to investigate inflammatory responses. According to gene expression and protein in HMVEC-Cs and HUVECs, IGF1R is more abundant than IR. Immunoprecipitation with anti-IGF1R antibody and immunoblotting with anti-IR antibody and vice versa, showed insulin/IGF1 hybrid receptors in HMVEC-Cs. IGF1 at a concentration of 10 K8 mol/l significantly stimulated phosphorylation of both IGF1R and IR in HMVEC-Cs. In HUVECs IGF1 10 K8 mol/l phosphorylated IGF1R. IGF1 stimulated DNA synthesis at 10 K8 mol/l and glucose accumulation at 10 K7 mol/l in HMVEC-Cs. TNF-a dramatically increased E-selectin expression, but no inflammatory or antiinflammatory effects of insulin, IGF1 or high glucose were seen. We conclude that HMVEC-Cs express more IGF1Rs than IRs, and mainly react to IGF1 due to the predominance of IGF1Rs and insulin/IGF1 hybrid receptors. TNF-a has a pronounced pro-inflammatory effect in HMVEC-Cs, which is not counteracted by insulin or IGF1.

Insulin uptake and action in microvascular endothelial cells of lymphatic and blood origin

“…Moreover, contrary to the extensively studied interaction of high insulin levels with endothelial cells derived from large blood vessels (30), there is scant information on the uptake or action of physiological doses of insulin by human microvascular endothelial cells in metabolically relevant tissues. A handful of studies have tested the action of supraphysiological insulin levels in human microvascular cells (4,14), and, notably, Gray et al (16) recently examined the effect of physiological insulin levels on human blood-brain barrier cells. In the present study, we evaluated the interaction of insulin with human, primary microvascular endothelial cells from lymphatic and blood origin, respectively, of dermal and adipose tissues, taking into consideration the doses of insulin that each cell type would be exposed to in vivo.…”

The South Asian Genome

“…Sequence variants in APOH are associated with LDL and triglyceride levels, and APOH plasma concentrations are elevated in people with T2D and metabolic syndrome [33]. IGF1 and IGF2 are growth factors which activate the insulin receptor [34], [35], whilst LYN is a tyrosine-kinase found in liver and adipose tissue which activates IRS1 leading to increased glucose utilisation [36], [37]. Our findings thus identify genetic variation amongst South Asians involving a cluster of genes linked to core metabolic traits including lipid metabolism, adipogenesis, insulin signalling and T2D.…”

Coronary microvascular dysfunction may be related to IGF-1 in acromegalic patients and can be restored by therapy

“…Coronary risk factors like hypertension, diabetes mellitus, and dyslipidemia are frequent in acromegaly, thus providing a possible link between GH/IGF-1 hypersecretion, vascular abnormalities and coronary artery disease (CAD) (4). IGF-1 is a potent mitogen for vascular smooth muscle cells (5) and stimulates the expression of adhesion molecules (6), a feature of endothelial dysfunction. On the other hand, IGF-1 stimulates nitric oxide production from both the endothelium and vascular smooth muscle cells (VSMC) (7).…”