Mechanisms of Cardiac Fibrosis in Inflammatory Heart Disease

Kania, Gabriela; Błyszczuk, Przemysław; Eriksson, Urs

doi:10.1016/j.tcm.2010.02.005

Cited by 157 publications

(100 citation statements)

References 45 publications

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“…Extracellular matrix remodeling and fibrosis are critical for the progression from CVB3 myocarditis to DCM (13,36,43). Fibroblast proliferation and collagen deposition can be increased by TNF, IL-1␤, IL-4, IL-13, IL-17A, and/or TGF-␤ 1 (7,13,18,40).…”

Section: Discussionmentioning

confidence: 99%

TLR3 deficiency induces chronic inflammatory cardiomyopathy in resistant mice following coxsackievirus B3 infection: role for IL-4

Abston

Coronado

Bucek

et al. 2013

American Journal of Physiology-Regulatory, Integrative and Comp

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Recent findings indicate that TLR3 polymorphisms increase susceptibility to enteroviral myocarditis and inflammatory dilated cardiomyopathy (iDCM) in patients. TLR3 signaling has been found to inhibit coxsackievirus B3 (CVB3) replication and acute myocarditis in mouse models, but its role in the progression from myocarditis to iDCM has not been previously investigated. In this study we found that TLR3 deficiency increased acute ( P = 5.9 × 10−9) and chronic ( P = 6.0 × 10−7) myocarditis compared with WT B6.129, a mouse strain that is resistant to chronic myocarditis and iDCM. Using left ventricular in vivo hemodynamic assessment, we found that TLR3-deficient mice developed progressively worse chronic cardiomyopathy. TLR3 deficiency significantly increased viral replication in the heart during acute myocarditis from day 3 through day 12 after infection, but infectious virus was not detected in the heart during chronic disease. TLR3 deficiency increased cytokines associated with a T helper (Th)2 response, including IL-4 ( P = 0.03), IL-10 ( P = 0.008), IL-13 ( P = 0.002), and TGF-β1 ( P = 0.005), and induced a shift to an immunoregulatory phenotype in the heart. However, IL-4-deficient mice had improved heart function during acute CVB3 myocarditis by echocardiography and in vivo hemodynamic assessment compared with wild-type mice, indicating that IL-4 impairs cardiac function during myocarditis. IL-4 deficiency increased regulatory T-cell and macrophage populations, including FoxP3+ T cells ( P = 0.005) and Tim-3+ macrophages ( P = 0.004). Thus, TLR3 prevents the progression from myocarditis to iDCM following CVB3 infection by reducing acute viral replication and IL-4 levels in the heart.

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Section: Discussionmentioning

confidence: 99%

TLR3 deficiency induces chronic inflammatory cardiomyopathy in resistant mice following coxsackievirus B3 infection: role for IL-4

Abston

Coronado

Bucek

et al. 2013

American Journal of Physiology-Regulatory, Integrative and Comp

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“…It has been shown that the increased collagens can activate the discoidin domain receptor (DDR) and therefore upregulate MMPs (43,46). In the heart, DDR 2 is primarily expressed in fibroblasts that are the major source of ECM components and MMPs (15,24). Similarly, MMP-13 (collagenase 3) was significantly increased by hypoxia in both fetal and neonatal hearts, whereas collagen III remained unchanged.…”

Section: Discussionmentioning

confidence: 99%

Maternal hypoxia alters matrix metalloproteinase expression patterns and causes cardiac remodeling in fetal and neonatal rats

Tong

Qin

et al. 2011

American Journal of Physiology-Heart and Circulatory Physiology

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Tong W, Xue Q, Li Y, Zhang L. Maternal hypoxia alters matrix metalloproteinase expression patterns and causes cardiac remodeling in fetal and neonatal rats. Am J Physiol Heart Circ Physiol 301: H2113-H2121, 2011. First published August 19, 2011 doi:10.1152/ajpheart.00356.2011.-Fetal hypoxia leads to progressive cardiac remodeling in rat offspring. The present study tested the hypothesis that maternal hypoxia results in reprogramming of matrix metalloproteinase (MMP) expression patterns and fibrillar collagen matrix in the developing heart. Pregnant rats were treated with normoxia or hypoxia (10.5% O2) from day 15 to 21 of gestation. Hearts were isolated from 21-day fetuses (E21) and postnatal day 7 pups (PD7). Maternal hypoxia caused a decrease in the body weight of both E21 and PD7. The heart-to-body weight ratio was increased in E21 but not in PD7. Left ventricular myocardium wall thickness and cardiomyocyte proliferation were significantly decreased in both fetal and neonatal hearts. Hypoxia had no effect on fibrillar collagen content in the fetal heart, but significantly increased the collagen content in the neonatal heart. Western blotting revealed that maternal hypoxia significantly increased collagen I, but not collagen III, levels in the neonatal heart. Maternal hypoxia decreased MMP-1 but increased MMP-13 and membrane type (MT)1-MMP in the fetal heart. In the neonatal heart, MMP-1 and MMP-13 were significantly increased. Active MMP-2 and MMP-9 levels and activities were not altered in either fetal or neonatal hearts. Hypoxia significantly increased tissue inhibitors of metalloproteinase (TIMP)-3 and TIMP-4 in both fetal and neonatal hearts. In contrast, TIMP-1 and TIMP-2 were not affected. The results demonstrate that in utero hypoxia reprograms the expression patterns of MMPs and TIMPs and causes cardiac tissue remodeling with the increased collagen deposition in the developing heart.

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“…Coronary arterial perivascular fibrosis is a serious complication of diabetes (24) that contributes to vascular dysfunction (19). Vascular remodeling with pathological fibrosis may be caused by increased collagen production and/or impaired collagen turnover due to deficient matrix metalloproteinase activation (31,36).…”

Section: Vascular Fibrosis and Stiffnessmentioning

confidence: 99%

“…Enhanced arginase activity appears to be involved in conditions characterized by vascular endothelial dysfunction (VED), such as diabetes, pulmonary hypertension, ischemia-reperfusion, and aging (5,19,29,33, 42). Additionally, high chronic L-arginine intake can induce arginase expression/activity, thereby inducing vascular dysfunction (20,21,30,35).…”

mentioning

confidence: 99%

Diabetes-induced vascular dysfunction involves arginase I

Romero¹,

Iddings²,

Platt³

et al. 2012

American Journal of Physiology-Heart and Circulatory Physiology

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Arginase can cause vascular dysfunction by competing with nitric oxide synthase for L-arginine and by increasing cell proliferation and collagen formation, which promote vascular fibrosis/stiffening. We have shown that increased arginase expression/activity contribute to vascular endothelial cell (EC) dysfunction. Here, we examined the roles of the two arginase isoforms, arginase I and II (AI and AII, respectively), in this process. Experiments were performed using streptozotocin-induced diabetic mice: wild-type (WT) mice and knockout mice lacking the AII isoform alone (AI ϩ/ϩ AII Ϫ/Ϫ ) or in combination with partial deletion of AI (AI ϩ/Ϫ AII Ϫ/Ϫ ). EC-dependent vasorelaxation of aortic rings and arterial fibrosis and stiffness were assessed in relation to arginase activity and expression. Diabetes reduced mean ECdependent vasorelaxation markedly in diabetic WT and AI ϩ/ϩ AII mice. In diabetic WT and AI ϩ/ϩ AII Ϫ/Ϫ mice, aortic arginase activity and AI expression were significantly increased compared with control mice, but neither parameter was altered in AI ϩ/Ϫ AII Ϫ/Ϫ mice. In summary, AI ϩ/Ϫ AII Ϫ/Ϫ mice exhibit better EC-dependent vasodilation and less vascular stiffness and coronary fibrosis compared with diabetic WT and AI ϩ/ϩ AII Ϫ/Ϫ mice. These data indicate a major involvement of AI in diabetes-induced vascular dysfunction. fibrosis; oxidative stress; vascular stiffness IN VASCULAR ENDOTHELIAL CELLS (ECs), nitric oxide (NO) synthase (NOS) uses L-arginine to produce NO, which maintains blood flow and reduces inflammation (21,22). Reduced availability of L-arginine to NOS and the resultant reduction of NO production have been implicated in the vascular dysfunction associated with diabetes and other cardiovascular disease states. Acute L-arginine supplementation can prevent or reverse EC dysfunction and restore EC-dependent vasodilation in diabetes (1, 31). Reduced availability of L-arginine for NOS can occur via increased activity or expression of arginase, an enzyme that competes with NOS for L-arginine, producing ornithine and urea.Two isoforms of arginase exist in mammals, arginase I and II (AI and AII, respectively) (8, 23). AI, which is located in the cytoplasm, is expressed most abundantly in liver, whereas AII is a mitochondrial enzyme expressed primarily in the kidney. Both AI and AII have been found in EC populations (11, 34). During diabetes, impaired vascular function is closely associated with oxidative stress and inflammation (12, 28), both of which have been associated with elevated arginase activity and expression (4, 18).Enhanced arginase activity appears to be involved in conditions characterized by vascular endothelial dysfunction (VED), such as diabetes, pulmonary hypertension, ischemia-reperfusion, and aging (5,19,29,33, 42). Additionally, high chronic L-arginine intake can induce arginase expression/activity, thereby inducing vascular dysfunction (20,21,30,35). Competition between arginase and NOS for their common substrate, arginine, suggests a cause-and-effect relationship in which...

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Mechanisms of Cardiac Fibrosis in Inflammatory Heart Disease

Cited by 157 publications

References 45 publications

TLR3 deficiency induces chronic inflammatory cardiomyopathy in resistant mice following coxsackievirus B3 infection: role for IL-4

TLR3 deficiency induces chronic inflammatory cardiomyopathy in resistant mice following coxsackievirus B3 infection: role for IL-4

Maternal hypoxia alters matrix metalloproteinase expression patterns and causes cardiac remodeling in fetal and neonatal rats

Diabetes-induced vascular dysfunction involves arginase I

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