Differential regulation of extracellular matrix constituents in myocardial remodeling with and without heart failure following pressure overload

Introduction: The heart undergoes myocardial remodeling during progression to heart failure following pressure overload. Myocardial remodeling is associated with structural and functional changes in cardiac myocytes, fibroblasts, and the extracellular matrix (ECM) and is accompanied by inflammation. Cardiac fibrosis, the accumulation of ECM molecules including collagens and collagen cross-linking, contributes both to impaired systolic and diastolic function. Insufficient mechanistic insight into what regulates cardiac fibrosis during pathological conditions has hampered therapeutic solutions. Lumican (LUM) is an ECM-secreted proteoglycan known to regulate collagen fibrillogenesis. Its expression in the heart is increased in clinical and experimental heart failure. Furthermore, LUM is important for survival and cardiac remodeling following pressure overload. We have recently reported that total lack of LUM increased mortality and left ventricular dilatation, and reduced collagen expression and cross-linking in LUM knockout mice after aortic banding (AB). Here, we examined the effect of LUM on myocardial remodeling and function following pressure overload in a less extreme mouse model, where cardiac LUM level was reduced to 50% (i.e., moderate loss of LUM). Methods and Results: mRNA and protein levels of LUM were reduced to 50% in heterozygous LUM (LUM+/–) hearts compared to wild-type (WT) controls. LUM+/– mice were subjected to AB. There was no difference in survival between LUM+/– and WT mice post-AB. Echocardiography revealed no striking differences in cardiac geometry between LUM+/– and WT mice 2, 4, and 6 weeks post-AB, although markers of diastolic dysfunction indicated better function in LUM+/– mice. LUM+/– hearts revealed reduced cardiac fibrosis assessed by histology. In accordance, the expression of collagen I and III, the main fibrillar collagens in the heart, and other ECM molecules central to fibrosis, i.e. including periostin and fibronectin, was reduced in the hearts of LUM+/– compared to WT 6 weeks post-AB. We found no differences in collagen cross-linking between LUM+/– and WT mice post-AB, as assessed by histology and qPCR. Conclusions: Moderate lack of LUM attenuated cardiac fibrosis and improved diastolic dysfunction following pressure overload in mice, adding to the growing body of evidence suggesting that LUM is a central profibrotic molecule in the heart that could serve as a potential therapeutic target.

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A tangled tale of microRNA and cardiac fibrosis

Clinical Science ◽

10.1042/cs20190866 ◽

2019 ◽

Vol 133 (21) ◽

pp. 2217-2220 ◽

Cited By ~ 2

Author(s):

Mark Chandy

Keyword(s):

Heart Failure ◽

Extracellular Matrix ◽

Wound Healing ◽

Cardiac Fibrosis ◽

Pressure Overload ◽

Clinical Science ◽

Therapeutic Options ◽

Diagnostic Modalities

Abstract Cardiac fibrosis is important for wound healing, regeneration and producing the extracellular matrix (ECM) that provides the scaffold for cells. In pathological situations, fibroblasts are activated and remodel the ECM. In volume 133, issue 17 of Clinical Science, Yang et al. discovered that the miR-214-3p/NLRC5 axis is important for fibroblast-to-myofibroblast transition (FMT) and ECM remodelling in a pressure overload model of fibrosis [Clin. Sci. (2019) 133(17), 1845–1856]. This discovery helps to explain the complicated regulation of cardiac fibrosis. It also underscores the need for more investigation into the mechanisms of cardiac fibrosis to develop better diagnostic modalities and therapeutic options in heart failure.

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Abstract 3158: Changes In Exracellular Matrix Regulation During Episodes Of Clinical Decompensation In Patients With Systolic Heart Failure

Circulation ◽

10.1161/circ.116.suppl_16.ii_709 ◽

2007 ◽

Vol 116 (suppl_16) ◽

Author(s):

Andreia Biolo ◽

Mark Fisch ◽

Joshua Balog ◽

Tania Chao ◽

David Denmark ◽

...

Keyword(s):

Oxidative Stress ◽

Heart Failure ◽

Extracellular Matrix ◽

Ventricular Remodeling ◽

Systolic Heart Failure ◽

Active Role ◽

Blood Levels ◽

Myocardial Remodeling ◽

And Oxidative Stress ◽

Selective Pattern

Introduction: The extracellular matrix (ECM) plays an active role in myocardial remodeling in heart failure (HF). Episodes of decompensation are associated with increased levels of neurohormones, inflammation and oxidative stress that are known to affect ECM regulation, and may contribute to progression of HF. We hypothesized that HF decompensation is associated with dysregulation of ECM turnover, as reflected by markers of degradation (matrix metalloproteinases [MMPs] and their tissue inhibitors [TIMPs]) and synthesis (pro-collagen N-terminal types I [PINP] and III [PIIINP]). Methods: Blood levels of MMP-2 and -9, TIMP-1, -2 and -4, and PI- and PIIINP were measured in 80 patients in 3 groups: 20 controls without HF, 21 patients with chronic stable systolic HF (no recent admission and no congestion by clinical examination), and 39 patients with acute HF decompensation, in whom measures were done on admission, at discharge, and chronically at least 2 months later. Results: In chronic stable HF, ECM markers were not increased vs. controls. In contrast, in patients with decompensated HF, MMP-2, TIMP-1 and PIIINP levels were increased (vs. stable HF or controls; Table ), while MMP-9, TIMP-2 and -4 or PINP were unchanged. Likewise, following effective therapy and return to clinical compensation (chronically but not at discharge) MMP-2, TIMP-1 and PIIINP levels returned to chronic stable HF levels, whereas MMP-9, TIMP-2 and -4 or PINP remained unchanged. Conclusion: A transient ECM dysregulation occurs during acute episodes of HF decompensation and may contribute to adverse ventricular remodeling. While HF decompensation is associated with certain markers of degradation and synthesis (MMP-2, TIMP-1 and PIIINP), other markers (MMP-9, TIMP-2 and -4 or PINP) are unchanged, suggesting selective pattern of ECM activation. The observation that matrix turnover is increased in decompensated but not stable HF may have implication for the timing of anti-remodeling therapy. ECM markers in controls, stable and decompensated HF

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EFFECT OF PINACIDIL ON MYOCARDIAL REMODELING IN PRESSURE OVERLOAD HEART FAILURE RAT MODEL: PP.1.28

Journal of Hypertension ◽

10.1097/01.hjh.0000378352.84573.6d ◽

2010 ◽

Vol 28 ◽

pp. e54-e55

Author(s):

N Chu ◽

SK Liu ◽

XM Wang

Keyword(s):

Heart Failure ◽

Rat Model ◽

Pressure Overload ◽

Myocardial Remodeling

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Extracellular Matrix in Cardiac Tissue Mechanics and Physiology: Role of Collagen Accumulation

10.5772/intechopen.96585 ◽

2021 ◽

Author(s):

Kristen LeBar ◽

Zhijie Wang

Keyword(s):

Heart Failure ◽

Mechanical Properties ◽

Extracellular Matrix ◽

Pressure Overload ◽

Volume Overload ◽

Tissue Mechanics ◽

Functional Changes ◽

Collagen Accumulation ◽

Heart Failure Progression

The extracellular matrix (ECM) forms a mesh surrounding tissue, made up of fibrous and non-fibrous proteins that contribute to the cellular function, mechanical properties of the tissue and physiological function of the organ. The cardiac ECM remodels in response to mechanical alterations (e.g., pressure overload, volume overload) or injuries (e.g., myocardial infarction, bacterial infection), which further leads to mechanical and functional changes of the heart. Collagen, the most prevalent ECM protein in the body, contributes significantly to the mechanical behavior of myocardium during disease progression. Alterations in collagen fiber morphology and alignment, isoform, and cross-linking occur during the progression of various cardiac diseases. Acute or compensatory remodeling of cardiac ECM maintains normal cardiac function. However, chronic or decompensatory remodeling eventually results in heart failure, and the exact mechanism of transition into maladaptation remains unclear. This review aims to summarize the primary role of collagen accumulation (fibrosis) in heart failure progression, with a focus on its effects on myocardial tissue mechanical properties and cellular and organ functions.

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The Extracellular Matrix in Ischemic and Nonischemic Heart Failure

Circulation Research ◽

10.1161/circresaha.119.311148 ◽

2019 ◽

Vol 125 (1) ◽

pp. 117-146 ◽

Cited By ~ 48

Author(s):

Nikolaos G. Frangogiannis

Keyword(s):

Heart Failure ◽

Extracellular Matrix ◽

Ejection Fraction ◽

Systolic Dysfunction ◽

Critical Role ◽

Pressure Overload ◽

Vascular Cells ◽

Force Transmission ◽

Ecm Proteins

The ECM (extracellular matrix) network plays a crucial role in cardiac homeostasis, not only by providing structural support, but also by facilitating force transmission, and by transducing key signals to cardiomyocytes, vascular cells, and interstitial cells. Changes in the profile and biochemistry of the ECM may be critically implicated in the pathogenesis of both heart failure with reduced ejection fraction and heart failure with preserved ejection fraction. The patterns of molecular and biochemical ECM alterations in failing hearts are dependent on the type of underlying injury. Pressure overload triggers early activation of a matrix-synthetic program in cardiac fibroblasts, inducing myofibroblast conversion, and stimulating synthesis of both structural and matricellular ECM proteins. Expansion of the cardiac ECM may increase myocardial stiffness promoting diastolic dysfunction. Cardiomyocytes, vascular cells and immune cells, activated through mechanosensitive pathways or neurohumoral mediators may play a critical role in fibroblast activation through secretion of cytokines and growth factors. Sustained pressure overload leads to dilative remodeling and systolic dysfunction that may be mediated by changes in the interstitial protease/antiprotease balance. On the other hand, ischemic injury causes dynamic changes in the cardiac ECM that contribute to regulation of inflammation and repair and may mediate adverse cardiac remodeling. In other pathophysiologic conditions, such as volume overload, diabetes mellitus, and obesity, the cell biological effectors mediating ECM remodeling are poorly understood and the molecular links between the primary insult and the changes in the matrix environment are unknown. This review article discusses the role of ECM macromolecules in heart failure, focusing on both structural ECM proteins (such as fibrillar and nonfibrillar collagens), and specialized injury-associated matrix macromolecules (such as fibronectin and matricellular proteins). Understanding the role of the ECM in heart failure may identify therapeutic targets to reduce geometric remodeling, to attenuate cardiomyocyte dysfunction, and even to promote myocardial regeneration.

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The role of matrix metalloproteinases in the myocardial remodeling

Cardiosomatics ◽

10.26442/22217185.2020.3.200374 ◽

2020 ◽

Vol 11 (3) ◽

pp. 22-28

Author(s):

Vladlen V. Bazylev ◽

Tatyana V. Kanaeva

Keyword(s):

Heart Failure ◽

Extracellular Matrix ◽

Matrix Metalloproteinases ◽

Cardiac Remodeling ◽

Prognostic Markers ◽

Enzyme System ◽

Therapeutic Targets ◽

Myocardial Remodeling ◽

Structural Event

The main structural event in the development of heart failure is the myocardial remodeling. The extracellular matrix, that was knows as, considered an inert framework of cardiomyocytes, plays an important role in cardiac remodeling. The enzyme system, primarily responsible for the degradation of the extracellular matrix, is a matrix metalloproteinases (MMP). This review examines the evidence for the participation of MMP in the myocardial remodeling and recent studies of MMP as prognostic markers. Regulation of induction and/or activation of MMP are potential therapeutic targets.

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