Effects of elevated glucose levels on interactions of cardiac fibroblasts with the extracellular matrix

Abstract

Exposure of fibroblasts to high glucose levels promotes a fibrotic response characterized by increased expression of extracellular matrix components including interstitial collagens. Little is known about the effects of glucose levels on other aspects of fibroblast function. Fibroblasts in the myocardium are surrounded by an extensive extracellular matrix composed predominantly of type I collagen. Interactions between fibroblasts and the myocardial extracellular matrix are thought to affect heart function by altering ventricular diastolic properties. The purpose of the present study was to determine the effects of elevated glucose levels on the interactions between heart fibroblasts and the collagenous extracellular matrix. Studies were performed to determine the effects of relative glucose levels on the ability of fibroblasts to migrate on and contract a three-dimensional collagenous substratum. These experiments illustrated that exposure of cardiac fibroblasts to high glucose levels (25 mM) resulted in decreased migratory activity of fibroblasts on a collagen matrix and decreased fibroblast proliferation. In addition, high glucose stimulated collagen and collagen-binding integrin expression and contraction of three-dimensional collagen gels by cardiac fibroblasts. These studies illustrate that altered glucose levels induce important changes in the interactions of cardiac fibroblasts with the collagenous extracellular matrix.

Metabolic regulation of collagen gel contraction by porcine aortic valvular interstitial cells

“…VICs are similar to those observed with cardiac fibroblasts, in which increased gel contraction was observed with an increase in glucose concentration from 1 to 4.5 g l 21 [22].…”

“…Because prior work with cardiac fibroblasts suggested that culture pre-treatment can increase cell contraction of collagen gels [22], cells were starved from glucose and pyruvate 24 h prior to gel preparation by replacing the medium with a (2glucose, 2pyruvate, þglutamine) DMEM solution containing 10% BGS, 1% antibiotic -antimycotic and 1% HEPES. Although our initial studies showed that depriving VICs of glucose for 24 h before collagen gel preparation did not appear to affect their collagen gel contraction behaviour, the withholding of glucose and pyruvate was performed prior to all experiments to avoid confounding results because those factors were being investigated.…”

Hyperglycemia enhances function and differentiation of adult rat cardiac fibroblasts

“…Collagen types I and III potently promoted CF migration, and plating on the collagen substrates had an equal additive effect on the hyperglycemia-induced CF migration. In contrast, neonatal fibroblasts plated on type I collagen and cultured in hyperglycemic media migrated slower than in normo-glycemic media (Zhang et al, 2007). This could be due to differences in the origin of fibroblasts and the type of migration assays i.e.…”

Investigating inherent functional differences between human cardiac fibroblasts cultured from nondiabetic and Type 2 diabetic donors

“…Although there are several reports describing in vitro effects of glucose concentration on CF function [13][14][15][16], the diabetic milieu is far more complex than hyperglycaemia alone and other factors such as hyperlipidaemia, advanced glycation end products, oxidative stress, proinflammatory cytokines, adipokines and profibrotic cytokines must also be considered [31].…”

“…There are several reports describing in vitro effects of elevated glucose concentration on CF function [13][14][15][16], however hyperglycaemia represents only one component of the complex diabetic milieu. Very recent evidence from rat and mouse models of T2DM has suggested that there are functional differences in CF derived from T2DM hearts compared with control hearts [17,18], however there is no current evidence that such differences exist in human CF.…”