Abstract
Heart failure (HF) is an increasingly recognized complication of diabetes. Cardiac fibrosis is an important causative mechanism of HF associated with diabetes. Recent data indicate that inflammation may be particularly important in the pathogenesis of cardiovascular fibrosis. We sought to determine the mechanism by which cardiac fibrosis develops and to specifically investigate the role of the CXCR4 axis in this process. Animals with type I diabetes (streptozotocin treated mice) or type II diabetes (Israeli Sand-rats) and controls were randomized to treatment with a CXCR4 antagonist, candesartan or vehicle control. Additional groups of mice also underwent bone marrow transplantation (GFP+ donor marrow) to investigate the potential role of bone marrow derived cell mobilization in the pathogenesis of cardiac fibrosis. Both type I and II models of diabetes were accompanied by the development of significant cardiac fibrosis. CXCR4 antagonism markedly reduced cardiac fibrosis in both models of diabetes, similar in magnitude to that seen with candesartan. In contrast to candesartan, the anti-fibrotic actions of CXCR4 antagonism occurred in a blood pressure independent manner. Whilst the induction of diabetes did not increase the overall myocardial burden of GFP+ cells, it was accompanied by an increase in GFP+ cells expressing the fibroblast marker alpha-smooth muscle actin and this was attenuated by CXCR4 antagonism. CXCR4 antagonism was also accompanied by increased levels of circulating regulatory T cells. Taken together the current data indicate that pharmacological inhibition of CXCR4 significantly reduces diabetes induced cardiac fibrosis, providing a potentially important therapeutic approach.
Highlights
In the setting of the continued rapid rise in the prevalence of obesity, diabetes mellitus has emerged as one of the fastest growing chronic diseases in the world [1]
Histological analysis of heart tissue showed that type I diabetes was associated with the development of extensive left ventricular perivascular fibrosis at 8 weeks (Fig 1A–1D) and this was attenuated by both candesartan and the CXCR4 antagonist, AMD3465
Bone marrow transplantation did not alter the fibrotic response to diabetes or the response to candesartan and AMD3465
Summary
In the setting of the continued rapid rise in the prevalence of obesity, diabetes mellitus has emerged as one of the fastest growing chronic diseases in the world [1]. The number of people with diabetes mellitus has more than doubled over the last few decades. It has become one of PLOS ONE | DOI:10.1371/journal.pone.0133616. The incidence of significant morbidity and mortality associated with diabetes is much worse than that in an age-matched healthy population. This largely reflects the well-known presence of a marked increase in cardiovascular disease prevalence [2]. There is a well established linkage between diabetes, obesity and cardiovascular disease, an independent linkage between diabetes and myocardial dysfunction, diabetic cardiomyopathy, is well recognized [3]
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