title: CXCR4 Antagonism Attenuates the Development of Diabetic Cardiac Fibrosis.
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.
authors.affiliation: Heart Failure Research Group, Baker IDI Heart and Diabetes Research Institute, Melbourne, Australia.
authors.forename: Po-Yin
authors.initials: PY
authors.lastname: Chu
authors.affiliation: Metabolic Research Unit, School of Medicine, Deakin University, Waurn Ponds, Victoria, Australia.
authors.forename: Ken
authors.initials: K
authors.lastname: Walder
authors.affiliation: Heart Failure Research Group, Baker IDI Heart and Diabetes Research Institute, Melbourne, Australia.
authors.forename: Duncan
authors.initials: D
authors.lastname: Horlock
authors.affiliation: Heart Failure Research Group, Baker IDI Heart and Diabetes Research Institute, Melbourne, Australia.
authors.forename: David
authors.initials: D
authors.lastname: Williams
authors.affiliation: Heart Failure Research Group, Baker IDI Heart and Diabetes Research Institute, Melbourne, Australia.
authors.forename: Erin
authors.initials: E
authors.lastname: Nelson
authors.affiliation: Heart Failure Research Group, Baker IDI Heart and Diabetes Research Institute, Melbourne, Australia.
authors.forename: Melissa
authors.initials: M
authors.lastname: Byrne
authors.affiliation: Diabetes Complications Division, Baker IDI Heart and Diabetes Research Institute, Melbourne, Australia.
authors.forename: Karin
authors.initials: K
authors.lastname: Jandeleit-Dahm
authors.affiliation: Clinical Diabetes and Epidemiology Department, Baker IDI Heart and Diabetes Research Institute, Melbourne, Australia.
authors.forename: Paul
authors.initials: P
authors.lastname: Zimmet
authors.affiliation: Heart Failure Research Group, Baker IDI Heart and Diabetes Research Institute, Melbourne, Australia.
authors.forename: David M
authors.initials: DM
authors.lastname: Kaye
mesh_terms: D047228:Angiotensin II Type 1 Receptor Blockers / Q000008:administration & dosage; D000818:Animals; D001562:Benzimidazoles / Q000008:administration & dosage; D001596:Benzylamines; D001713:Biphenyl Compounds; D016026:Bone Marrow Transplantation; D054377:Chemokine CXCL12; D000080027:Cyclams; D058065:Diabetic Cardiomyopathies / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology* / Q000503:physiopathology; D004195:Disease Models, Animal; D005355:Fibrosis; D006352:Heart Ventricles / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D006439:Hemodynamics / Q000187:drug effects; D006571:Heterocyclic Compounds / Q000008:administration & dosage; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D058628:Myofibroblasts / Q000378:metabolism / Q000473:pathology; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors*; D013777:Tetrazoles / Q000008:administration & dosage
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D001562:Benzimidazoles; D001596:Benzylamines; D001713:Biphenyl Compounds; D054377:Chemokine CXCL12; D000080027:Cyclams; D006571:Heterocyclic Compounds; D019718:Receptors, CXCR4; D013777:Tetrazoles; C081643:candesartan; C088327:plerixafor