Type II diabetes promotes a myofibroblast phenotype in cardiac fibroblasts

Abstract

Aims Cardiovascular disease is the leading cause of death for individuals diagnosed with type II diabetes mellitus (DM). Changes in cardiac function, left ventricular wall thickness and fibrosis have all been described in patients and animal models of diabetes; however, the factors mediating increased matrix deposition remain unclear. The goal of this study was to evaluate whether cardiac fibroblast function is altered in a rat model of type II DM. Main methods Cardiac fibroblasts were isolated from 14 week old Zucker diabetic and lean control (LC) adult male rat hearts. Fibroblasts were examined for their ability to remodel 3-dimensional collagen matrices, their adhesion, migration and proliferation on collagen and changes in gene expression associated with collagen remodeling. Key findings Cardiac fibroblasts from diabetic animals demonstrated significantly greater ability to contract 3-dimensional collagen matrices compared to cardiac fibroblasts from LC animals. The enhanced contractile behavior was associated with an increase in diabetic fibroblast proliferation and elevated expression of α-smooth muscle actin and type I collagen, suggesting the transformation of diabetic fibroblasts into a myofibroblast phenotype. Significance Cardiac fibrosis is a common complication in diabetic cardiomyopathy which may contribute to the observed cardiac dysfunction associated with this disease. Identifying and understanding the changes in fibroblast behavior which contribute to the increased deposition of collagen and other matrix proteins may provide novel therapeutic targets for reducing the devastating effects of diabetes on the heart.

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

“…Changes were relatively small, but included increased contractile behaviour, increased SMA and type I collagen expression and increased cell proliferation in the diabetic cells [17]. Very recently, in a study using a murine model of T2DM (db/db mouse), CF derived from db/db hearts were shown to have elevated expression of several pro-fibrotic markers (type I collagen, PAI-1, TGF-, TIMP-2) compared with cells derived from db/wt littermates [18].…”

“…Using fibroblasts cultured from the hearts of Zucker diabetic rats, a laboratory model of T2DM, it was recently demonstrated that diabetic cells adopt a more myofibroblast-like phenotype compared with cells derived from lean control hearts [17]. Changes were relatively small, but included increased contractile behaviour, increased SMA and type I collagen expression and increased cell proliferation in the diabetic cells [17].…”

“…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.…”

Inflammatory and fibrotic responses of cardiac fibroblasts to myocardial damage associated molecular patterns (DAMPs)

“…For example, AGE-modified proteins can induce CF proliferation and collagen production in an angiotensin II-dependent manner [23]. Several recent studies on CF derived from type 2 diabetic patients or diabetic animal models have reported that fibroblasts from diabetic hearts possess an inherent pro-fibrotic phenotype, including elevated collagen synthesis, myofibroblast transdifferentiation and, in some cases, upregulation of RAGE expression [24,78,129,130].…”

Using basic fibroblast growth factor nanoliposome combined with ultrasound-introduced technology to early intervene the diabetic cardiomyopathy

“…1,2 The structural changes included fibrosis, apoptosis, and angiopathy of myocytes, and the functional changes included endothelium-myocytes uncoupling, impairment of contractility of cardiomyocytes, decrease in survival and differentiation of cardiac stem cells, and diastolic and systolic dysfunction. [3][4][5] Nonetheless, the pathophysiology of DCM remains uncertain and novel therapeutic strategies for its prevention and rescue are urgently needed.…”