CXCR4 Antagonism Attenuates the Development of Diabetic Cardiac Fibrosis

Chu, Po‐Yin; Walder, Ken; Horlock, Duncan; Williams, David R.; Nelson, Erin M.; Byrne, Melissa; Jandeleit‐Dahm, Karin; Zimmet, Paul; Kaye, David M.

doi:10.1371/journal.pone.0133616

Cited by 47 publications

(43 citation statements)

References 39 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In terms of the amount of collagen, there was evidence of cellular and interstitial brosis in this experimental model, as found elsewhere for animals with diabetes [53]. Reduced myocyte hypertrophy and decreased collagen deposition ( brosis), evidencing cardiac damage, was observed in Sprague-Dawley rats trained at 80% of their maximum capacity for four weeks, showing that the high-intensity exercise was able to reverse cardiac remodeling in the diabetic heart [52].…”

Section: Discussionsupporting

confidence: 83%

Swimming Exercise Modifies Oxidative Stress in Skeletal and Cardiac Muscles of Diabetic Rats

Pio

Orzari²,

Alves

et al. 2020

Preprint

View full text Add to dashboard Cite

Abstract Background: Oxidative stress is a key factor in the worsening of diabetes, requiring an increase in the activity of the antioxidant system, culminating in a balance in the body. The aim of the present study was to evaluate the redox state in the skeletal and cardiac muscles in rats induced to diabetes model and submitted to swimming exercise training for 4 weeks. Methods: Wistar rats were separated into the following four groups: untrained control (C); trained control (T); untrained alloxan-induced diabetes (D); trained alloxan-induced diabetes (TD). The animals were submitted to swimming exercise training for 4 weeks. The redox state of skeletal and cardiac muscles was analyzed by TBARS, -SH groups and, H2O2 production as well as by the SOD and Catalase activity. Besides, a histomorphometry analysis was performed in the cardiac muscle in which the total number of cardiomyocytes and the total area of collagen fibers were measured.Results: On the Soleus muscles, the TD group showed increased of H2O2 and Catalase compared to T group; and SOD compared to D group. About the red gastrocnemius, TD group presented higher SOD and lower Catalase relation to D group. Regarding to cardiac muscle, TD group presented lower TBARS than D group, while it was higher in -SH groups and Catalase compared to D group. Moreover, the swimming exercise led to a decrease in hyperglycemia, benefits in pathogenesis and physio-pathogenesis, evidenced by a reduced number of cardiomyocytes and area of collagen fibers. Conclusions: The swimming protocol exercise in diabetic rats was able to control the hyperglycemia, control of oxidative damage and minimize the fibrosis on cardiac muscle in diabetic rats.

show abstract

Section: Discussionsupporting

confidence: 83%

Swimming Exercise Modifies Oxidative Stress in Skeletal and Cardiac Muscles of Diabetic Rats

Pio

Orzari²,

Alves

et al. 2020

Preprint

View full text Add to dashboard Cite

show abstract

“…Is there evidence that the effects of the SDF‐1α/CXCR4 receptor axis on CFs, PGVSMCs, and GMCs observed in the present study may translate to increased cardiac and renal fibrosis in vivo? Although there is evidence that knockdown of CXCR4 receptors specifically in cardiomyoctes reduces cardiac fibrosis, studies by Chu et al demonstrated that, in mice, antagonism of CXCR4 receptors reduces cardiorenal fibrosis in mineralocorticoid‐induced hypertension and cardiac fibrosis in type 1 and 2 diabetes mellitus . Moreover, experiments by Zuk et al showed that blockade of CXCR4 receptors decreases renal fibrosis due to kidney injury.…”

Section: Discussionmentioning

confidence: 99%

“…cardiac fibrosis, 20 studies by Chu et al demonstrated that, in mice, antagonism of CXCR4 receptors reduces cardiorenal fibrosis in mineralocorticoid-induced hypertension 21 and cardiac fibrosis in type 1 and 2 diabetes mellitus. 22 Moreover, experiments by Zuk et al 23 showed that blockade of CXCR4 receptors decreases renal fibrosis due to kidney injury. In addition, Yuan et al 24 reported that CXCR4 receptor expression is increased in ureteral obstruction and that CXCR4 receptor knockout prevents hydronephrosis-induced renal fibrosis.…”

Section: Discussionmentioning

confidence: 99%

SDF‐1α (Stromal Cell‐Derived Factor 1α) Induces Cardiac Fibroblasts, Renal Microvascular Smooth Muscle Cells, and Glomerular Mesangial Cells to Proliferate, Cause Hypertrophy, and Produce Collagen

Jackson

Zhang

Gillespie

et al. 2017

JAHA

View full text Add to dashboard Cite

BackgroundActivated cardiac fibroblasts (CFs), preglomerular vascular smooth muscle cells (PGVSMCs), and glomerular mesangial cells (GMCs) proliferate, cause hypertrophy, and produce collagen; in this way, activated CFs contribute to cardiac fibrosis, and activated PGVSMCs and GMCs promote renal fibrosis. In heart and kidney diseases, SDF‐1α (stromal cell‐derived factor 1α; endogenous CXCR4 [C‐X‐C motif chemokine receptor 4] receptor agonist) levels are often elevated; therefore, it is important to know whether and how the SDF‐1α/CXCR4 axis activates CFs, PGVSMCs, or GMCs.Methods and ResultsHere we investigated whether SDF‐1α activates CFs, PGVSMCs, and GMCs to proliferate, hypertrophy, or produce collagen. DPP4 (dipeptidyl peptidase 4) inactivates SDF‐1α and previous experiments show that growth‐promoting peptides have greater effects in cells from genetically‐hypertensive animals. Therefore, we performed experiments in the absence and presence of sitagliptin (DPP4 inhibitor) and in cells from normotensive Wistar–Kyoto rats and spontaneously hypertensive rats. Our studies show (1) that spontaneously hypertensive and Wistar–Kyoto rat CFs, PGVSMCs, and GMCs express CXCR4 receptors and DPP4 activity; (2) that chronic treatment with physiologically relevant concentrations of SDF‐1α causes concentration‐dependent increases in the proliferation (cell number) and hypertrophy (3H‐leucine incorporation) of and collagen production (3H‐proline incorporation) by CFs, PGVSMCs, and GMCs; (3) that sitagliptin augments these effects of SDF‐1α; (4) that interactions between SDF‐1α and sitagliptin are greater in spontaneously hypertensive rat cells; (5) that CXCR4 antagonism (AMD3100) blocks all effects of SDF‐1α; and (6) that SDF‐1α/CXCR4 signal transduction likely involves the RACK1 (receptor for activated C kinase 1)/Gβγ/PLC (phospholipase C)/PKC (protein kinase C) signaling complex.ConclusionsThe SDF‐1α/CXCR4 axis drives proliferation and hypertrophy of and collagen production by CFs, PGVSMCs, and GMCs, particularly in cells from genetically hypertensive animals and when DPP4 is inhibited.

show abstract

“…Although myocardial MCP-1 expression was increased in a rat model of type 2 diabetes [106], whether induction of the chemokine plays a critical role in fibrosis of the diabetic heart has not been investigated. SDF-1 blockade through inhibition of its receptor CXCR4 attenuated cardiac fibrosis in rodent models of type 1 and type 2 diabetes [107]. …”

Section: Molecular Signals Implicated In Diabetes-associated Cardimentioning

confidence: 99%

Diabetes-associated cardiac fibrosis: Cellular effectors, molecular mechanisms and therapeutic opportunities

Russo

Frangogiannis

2016

Journal of Molecular and Cellular Cardiology

380

299

View full text Add to dashboard Cite

Both type 1 and type 2 diabetes are associated with cardiac fibrosis that may reduce myocardial compliance, contribute to the pathogenesis of heart failure, and trigger arrhythmic events. Diabetes-associated fibrosis is mediated by activated cardiac fibroblasts, but may also involve fibrogenic actions of macrophages, cardiomyocytes and vascular cells. The molecular basis responsible for cardiac fibrosis in diabetes remains poorly understood. Hyperglycemia directly activates a fibrogenic program, leading to accumulation of advanced glycation end-products (AGEs) that crosslink extracellular matrix proteins, and transduce fibrogenic signals through reactive oxygen species generation, or through activation of Receptor for AGEs (RAGE)-mediated pathways. Pro-inflammatory cytokines and chemokines may recruit fibrogenic leukocyte subsets in the cardiac interstitium. Activation of transforming growth factor-β/Smad signaling may activate fibroblasts inducing deposition of structural extracellular matrix proteins and matricellular macromolecules. Adipokines, endothelin-1 and the renin-angiotensin-aldosterone system have also been implicated in the diabetic myocardium. This manuscript reviews our current understanding of the cellular effectors and molecular pathways that mediate fibrosis in diabetes. Based on the pathophysiologic mechanism, we propose therapeutic interventions that may attenuate the diabetes-associated fibrotic response and discuss the challenges that may hamper clinical translation.

show abstract

CXCR4 Antagonism Attenuates the Development of Diabetic Cardiac Fibrosis

Cited by 47 publications

References 39 publications

Swimming Exercise Modifies Oxidative Stress in Skeletal and Cardiac Muscles of Diabetic Rats

Swimming Exercise Modifies Oxidative Stress in Skeletal and Cardiac Muscles of Diabetic Rats

SDF‐1α (Stromal Cell‐Derived Factor 1α) Induces Cardiac Fibroblasts, Renal Microvascular Smooth Muscle Cells, and Glomerular Mesangial Cells to Proliferate, Cause Hypertrophy, and Produce Collagen

Diabetes-associated cardiac fibrosis: Cellular effectors, molecular mechanisms and therapeutic opportunities

Contact Info

Product

Resources

About