Dilated Cardiomyopathy Is Associated With Significant Changes in Collagen Type I/III ratio

Pauschinger, Matthias; Knopf, Dagmar; Petschauer, S.; Doerner, Andrea; Poller, Wolfgang; Schwimmbeck, Peter L.; Kühl, Uwe; Schultheiß, H.-P.

doi:10.1161/01.cir.99.21.2750

Cited by 310 publications

(214 citation statements)

References 24 publications

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“…Considering that all patients presented systolic dysfunction, we demonstrated that with more type I collagen, which is associated with strength and stiffness, the left ventricular ejection fraction is worse. On the other hand, a previous study of dilated cardiomyopathy with left ventricular ejection fraction lower than 50% presented increased I/III ratio, and related this finding to systolic and diastolic dysfunction (38). What seems to be contradictory, at first analysis, is that the normal myocardium had a lower proportion of collagen III/I mRNA compared with that in the dilated cardiomyopathy groups.…”

Section: Collagen Type Iii/i Expression Ratiomentioning

confidence: 86%

Collagen content, but not the ratios of collagen type III/I mRNAs, differs among hypertensive, alcoholic, and idiopathic dilated cardiomyopathy

Soufen

Salemi

Aneas

et al. 2008

Braz J Med Biol Res

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Cardiac interstitial fibrosis may contribute to ventricular dysfunction and the prognosis of patients with dilated cardiomyopathy. The objective of the present study was to determine if total myocardial collagen content and collagen type III/I (III/I ratio) mRNAs differ in hypertensive, alcoholic, and idiopathic dilated cardiomyopathy subjects. Echocardiography and exercise cardiopulmonary testing were performed in patients with idiopathic (N = 22), hypertensive (N = 12), and alcoholic (N = 11) dilated cardiomyopathy. Morphometric analysis of collagen was performed in fragments obtained by endomyocardial biopsy with picrosirius red staining. The collagen III/I ratio was determined by reverse transcription polymerase chain reaction. Samples of controls (N = 10) were obtained from autopsy. Echocardiographic variables and maximal oxygen uptake were not different among dilated cardiomyopathy groups. Collagen was higher in all dilated cardiomyopathy groups (idiopathic, hypertensive and alcoholic, , , , , 7.36 ± 1.09%) versus controls (1.12 ± 0.18%), P < 0.05. Collagen was lower in idiopathic dilated cardiomyopathy (4.97 ± 0.83%) than hypertensive (8.50 ± 1.11%) and alcoholic (10.77 ± 2.09%) samples (P < 0.005 for both). The collagen III/I ratio in all samples from dilated cardiomyopathy patients was higher compared to that in controls (0.29 ± 0.04, P < 0.05) but was the same in the samples from idiopathic (0.77 ± 0.07), hypertensive (0.75 ± 0.07), and alcoholic (0.81 ± 0.16) dilated cardiomyopathy groups. Because of the different physical properties of the types of collagen, the higher III/I ratio may contribute to progressive ventricular dilation and dysfunction in dilated cardiomyopathy patients.

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Section: Collagen Type Iii/i Expression Ratiomentioning

confidence: 86%

Collagen content, but not the ratios of collagen type III/I mRNAs, differs among hypertensive, alcoholic, and idiopathic dilated cardiomyopathy

Soufen

Salemi

Aneas

et al. 2008

Braz J Med Biol Res

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“…Sirius Red staining Total collagen content of the Sirius Red (Polyscience, Warrington, PA, USA) stained sections was measured under circularly polarised light according to previously published methods [18] and quantified by digital image analysis as described in detail elsewhere [19]. Perivascular fibrosis was not measured.…”

Section: Methodsmentioning

confidence: 99%

Anti-inflammatory effects of atorvastatin improve left ventricular function in experimental diabetic cardiomyopathy

et al. 2007

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Aims/hypothesis Emerging evidence suggests that statins exert beneficial effects beyond those predicted by their cholesterollowering actions. We investigated whether atorvastatin influences the development of left ventricular (LV) dysfunction, independently of cholesterol-lowering, in an experimental model of type 1 diabetes mellitus cardiomyopathy. Methods Streptozotocin-induced diabetic rats were treated with atorvastatin (50 mg/kg daily, orally) or with vehicle for 6 weeks. LV function was analysed using tip-catheter measurements. Cardiac stainings of TNF-α, IL-1β, intercellular adhesion molecule-1, vascular cellular adhesion molecule-1, CD11a/lymphocyte-associated antigen-1, CD11b/ macrophage antigen alpha, CD18/β2-integrin, ED1/CD68, collagen I and III, and Sirius Red were assessed by digital image analysis. Ras-related C3 botulinum toxin substrate (RAC1) and ras homologue gene family, member A (RHOA) activities were determined by RAC1 glutathione-S-transferasep21-activated kinase and rhotekin pull-down assays, respectively. Cardiac lipid peroxides were measured by a colorimetric assay. The phosphorylation state of p38 mitogen-activated protein kinase (MAPK) and endothelial nitric oxide synthase (eNOS) protein production were analysed by western blot. Results Diabetes was associated with induced cardiac stainings of TNF-α, IL-1β, cellular adhesion molecules, increased leucocyte infiltration, macrophage residence and cardiac collagen content. In contrast, atorvastatin reduced both intramyocardial inflammation and myocardial fibrosis, resulting in improved LV function. This effect was paralleled with a normalisation of diabetes-induced RAC1 and RHOA activity, in the absence of LDL-cholesterol lowering. In addition, atorvastatin decreased diabetesinduced cardiac lipid peroxide levels and p38 MAPK phosphorylation by 1.3-fold (p<0.05) and 3.2-fold (p<0.0005), respectively, and normalised the reduced eNOS production caused by diabetes. Conclusions/interpretation These data indicate that atorvastatin, independently of its LDL-cholesterol-lowering capacity, reduces intramyocardial inflammation and myocardial fibrosis, resulting in improved LV function in an experimental model of diabetic cardiomyopathy.

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“…Whereas collagen III forms an elastic network storing kinetic energy as elastic recoil, collagen I represents a stiff fibrillar protein providing tensile strength. 25,26 Only the collagen I and not the collagen III promoter is studded with SP-1-binding sites. Therefore, the differential increase of collagen I over collagen III in galectin-3-infused animals could be explained by the possible differences in the molecular makeup of their promoter sites.…”

Section: Significance Of Interstitial Fibrosis and Collagen I Productmentioning

confidence: 99%

Galectin-3 Marks Activated Macrophages in Failure-Prone Hypertrophied Hearts and Contributes to Cardiac Dysfunction

et al. 2004

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Background-Inflammatory mechanisms have been proposed to be important in heart failure (HF), and cytokines have been implicated to add to the progression of HF. However, it is unclear whether such mechanisms are already activated when hypertrophied hearts still appear well-compensated and whether such early mechanisms contribute to the development of HF. Methods and Results-In a comprehensive microarray study, galectin-3 emerged as the most robustly overexpressed gene in failing versus functionally compensated hearts from homozygous transgenic TGRmRen2-27 (Ren-2) rats. Myocardial biopsies obtained at an early stage of hypertrophy before apparent HF showed that expression of galectin-3 was increased specifically in the rats that later rapidly developed HF. Galectin-3 colocalized with activated myocardial macrophages. We found galectin-3-binding sites in rat cardiac fibroblasts and the extracellular matrix. Recombinant galectin-3 induced cardiac fibroblast proliferation, collagen production, and cyclin D1 expression. A 4-week continuous infusion of low-dose galectin-3 into the pericardial sac of healthy Sprague-Dawley rats led to left ventricular dysfunction, with a 3-fold differential increase of collagen I over collagen III. Myocardial galectin-3 expression was increased in aortic stenosis patients with depressed ejection fraction. Conclusions-This study shows that an early increase in galectin-3 expression identifies failure-prone hypertrophied hearts. Galectin-3, a macrophage-derived mediator, induces cardiac fibroblast proliferation, collagen deposition, and ventricular dysfunction. This implies that HF therapy aimed at inflammatory responses may need to be targeted at the early stages of HF and probably needs to antagonize multiple inflammatory mediators, including galectin-3.

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Dilated Cardiomyopathy Is Associated With Significant Changes in Collagen Type I/III ratio

Abstract: Differential increase of Col I and Col III leads to an increased Col I/Col III ratio in DCM myocardium. Because Col I provides substantial tensile strength and stiffness, this may contribute to systolic and in particular diastolic dysfunction in DCM.

Cited by 310 publications

References 24 publications

Collagen content, but not the ratios of collagen type III/I mRNAs, differs among hypertensive, alcoholic, and idiopathic dilated cardiomyopathy

Collagen content, but not the ratios of collagen type III/I mRNAs, differs among hypertensive, alcoholic, and idiopathic dilated cardiomyopathy

Anti-inflammatory effects of atorvastatin improve left ventricular function in experimental diabetic cardiomyopathy

Galectin-3 Marks Activated Macrophages in Failure-Prone Hypertrophied Hearts and Contributes to Cardiac Dysfunction

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