Cardiomyocyte-specific transgenic expression of lysyl oxidase-like protein-1 induces cardiac hypertrophy in mice

Ohmura, Haruya; Yasukawa, Hideo; Minami, Tetsuro; Sugi, Yusuke; Oba, Toyoharu; Nagata, T.; Kyogoku, Sachiko; Ohshima, Hideki; Aoki, Hiroki; Imaizumi, Tsutomu

doi:10.1038/hr.2012.92

Cited by 21 publications

(14 citation statements)

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“…In recent years, new factors have been identified and characterized that trigger and maintain the myocardial fibrotic response in different cardiac diseases . An important role in pathological cardiac fibrosis was recently described for the lysyl oxidase (Lox) family of enzymes, which catalyze collagen assembly . Here, we show that suppression of cardiac Cn impairs the transcriptional expression of Lox , which is involved in the progression of a pathological fibrotic response in the heart.…”

Section: Discussionmentioning

confidence: 73%

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Cardiomyocyte calcineurin is required for the onset and progression of cardiac hypertrophy and fibrosis in adult mice

et al. 2018

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Previous studies have demonstrated that activation of calcineurin induces pathological cardiac hypertrophy (CH). In these studies, loss‐of‐function was mostly achieved by systemic administration of the calcineurin inhibitor cyclosporin A. The lack of conditional knockout models for calcineurin function has impeded progress toward defining the role of this protein during the onset and the development of CH in adults. Here, we exploited a mouse model of CH based on the infusion of a hypertensive dose of angiotensin II (AngII) to model the role of calcineurin in CH in adulthood. AngII‐induced CH in adult mice was reduced by treatment with cyclosporin A, without affecting the associated increase in blood pressure, and also by induction of calcineurin deletion in adult mouse cardiomyocytes, indicating that cardiomyocyte calcineurin is required for AngII‐induced CH. Surprisingly, cardiac‐specific deletion of calcineurin, but not treatment of mice with cyclosporin A, significantly reduced AngII‐induced cardiac fibrosis and apoptosis. Analysis of profibrotic genes revealed that AngII‐induced expression of Tgfβ family members and Lox was not inhibited by cyclosporin A but was markedly reduced by cardiac‐specific calcineurin deletion. These results show that AngII induces a direct, calcineurin‐dependent prohypertrophic effect in cardiomyocytes, as well as a systemic hypertensive effect that is independent of calcineurin activity.

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Section: Discussionmentioning

confidence: 73%

“…In recent years, new factors have been identified and characterized that trigger and maintain the myocardial fibrotic response in different cardiac diseases [59]. An important role in pathological cardiac fibrosis was recently described for the lysyl oxidase (Lox) family of enzymes, which catalyze collagen assembly [34,[60][61][62][63].…”

Section: Discussionmentioning

confidence: 99%

Cardiomyocyte calcineurin is required for the onset and progression of cardiac hypertrophy and fibrosis in adult mice

et al. 2018

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“…Similarly, Ang II-induced cardiac hypertrophy was exacerbated in transgenic mice that overexpress LOXL1 specifically in cardiomyocytes, which exhibited myocyte hypertrophy, and higher mRNA levels of brain natriuretic peptide (Bnp) than their WT littermates. Echocardiographic data evidenced that LOXL1 transgenesis caused an increase in wall thickness with preserved cardiac contraction [26]. It should be noted that Loxl1 expression is induced by hypertrophic agonists in cardiomyocytes in culture, and, in vivo, in a rat model of hypertrophy induced by abdominal aortic constriction.…”

Section: Lox and Loxls In Dilated And Hypertrophic Cardiomyopathies Amentioning

confidence: 90%

“…Knockout mice for LOXL1, the closest mammal paralog of LOX, show an altered post-partum deposition of elastic fibers in pelvic organs associated with pelvic organ prolapse, emphysematous lungs and skin laxity, as well as vascular abnormalities, although less serious than those detected in Lox −/− mice [25]. In turn, transgenic mice with cardiomyocyte-specific expression of LOXL1 developed cardiac hypertrophy [26]. Deletion of LOXL2 in mice increases perinatal death in nearly half of newborn animals, associated with dramatic alterations in the heart (disrupted ventricular septa) [27], while, unexpectedly, animals surviving the perinatal period grow without any major pathological manifestation.…”

Section: Lox Isoenzymes In the Cardiovascular Systemmentioning

confidence: 99%

The Role of Lysyl Oxidase Enzymes in Cardiac Function and Remodeling

Rodrı́guez

Martínez-González

2019

Cells

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Lysyl oxidase (LOX) proteins comprise a family of five copper-dependent enzymes (LOX and four LOX-like isoenzymes (LOXL1-4)) critical for extracellular matrix (ECM) homeostasis and remodeling. The primary role of LOX enzymes is to oxidize lysyl and hydroxylysyl residues from collagen and elastin chains into highly reactive aldehydes, which spontaneously react with surrounding amino groups and other aldehydes to form inter-and intra-catenary covalent cross-linkages. Therefore, they are essential for the synthesis of a mature ECM and assure matrix integrity. ECM modulates cellular phenotype and function, and strikingly influences the mechanical properties of tissues. This explains the critical role of these enzymes in tissue homeostasis, and in tissue repair and remodeling. Cardiac ECM is mainly composed of fibrillar collagens which form a complex network that provides structural and biochemical support to cardiac cells and regulates cell signaling pathways. It is now becoming apparent that cardiac performance is affected by the structure and composition of the ECM and that any disturbance of the ECM contributes to cardiac disease progression. This review article compiles the major findings on the contribution of the LOX family to the development and progression of myocardial disorders. part of the mechanoresponsive gene programs responsible for the mechanical regulation of gene expression in cardiac myocytes and fibroblasts [11]. Thus, LOX/LOXLs contribute to cardiac fibrosis, but are also active players involved in the cellular mechanisms underlying cardiac dysfunction and disease progression.In the last years, multiple studies have contributed to the understanding of the pathophysiological role of the LOX family in human diseases and, in particular, in the cardiovascular system. The involvement of this family on vascular diseases has been recently reviewed [12]. Further, LOX/LOXLs participate in a variety of processes affecting the heart, from those associated to post-myocardial infarction (MI) cardiac remodeling, cardiac hypertrophy triggered by pressure or volume overload, heart failure (HF) with preserved ejection fraction (HFPEF) associated with obesity and metabolic syndrome or atrial fibrillation. The strong impact of the alteration of LOX/LOXLs on CCL and heart function supports the interest of these family of enzymes as pharmacological targets to improve cardiac remodeling and slow the progression to HF. In this review article we focus on those findings that support the fundamental involvement of the LOX family in the mechanisms underlying cardiac damage and repair. The LOX Family of ECM-Modifying EnzymesLOX is an extracellular enzyme which governs the post-translational modification of ECM collagen and elastin. LOX catalyzes the oxidative deamination of specific ε-amino groups of lysine and hydroxylysine residues in collagen and elastin. This leads to the generation of highly reactive peptidyl α-aminoadipic γ-semialdehydes and the release of hydrogen peroxide as by-product [1-3] (Figure 1). This reactio...

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“…LOXL1 regulates collagen cross-linking and total collagen levels in angiotensin II-induced hypertension in rodents [60], has been associated with renal fibrosis [61], and when overexpressed, induces cardiac hypertrophy in mice [62]. LOXL2 was reported to increase collagen accumulation in breast and glioma tumors [63,64], and has been associated with liver fibrosis [65], as well as IPF [64].…”

Section: Reviewmentioning

confidence: 99%

Matrix regulation of idiopathic pulmonary fibrosis: the role of enzymes

Clarke

Carruthers

Mustelin³

et al. 2013

Fibrogenesis Tissue Repair

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Repairing damaged tissues is an essential homeostatic mechanism that enables clearance of dead or damaged cells after injury, and the maintenance of tissue integrity. However, exaggeration of this process in the lung can lead to the development of fibrotic scar tissue. This is characterized by excessive accumulation of extracellular matrix (ECM) components such as fibronectin, proteoglycans, hyaluronic acid, and interstitial collagens. After tissue injury, or a breakdown of tissue integrity, a cascade of events unfolds to maintain normal tissue homeostasis. Inflammatory mediators are released from injured epithelium, leading to both platelet activation and inflammatory cell migration. Inflammatory cells are capable of releasing multiple pro-inflammatory and fibrogenic mediators such as transforming growth factor (TGF)β and interleukin (IL)-13, which can trigger myofibroblast proliferation and recruitment. The myofibroblast population is also expanded as a result of epithelial cells undergoing epithelial-to-mesenchymal transition and of the activation of resident fibroblasts, leading to ECM deposition and tissue remodeling. In the healthy lung, wound healing then proceeds to restore the normal architecture of the lung; however, fibrosis can develop when the wound is severe, the tissue injury persists, or the repair process becomes dysregulated. Understanding the processes regulating aberrant wound healing and the matrix in the chronic fibrotic lung disease idiopathic pulmonary fibrosis (IPF), is key to identifying new treatments for this chronic debilitating disease. This review focuses primarily on the emerging role of enzymes in the lungs of patients with IPF. Elevated expression of a number of enzymes that can directly modulate the ECM has been reported, and recent data indicates that modulating the activity of these enzymes can have a downstream effect on fibrotic tissue remodeling.

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Cardiomyocyte-specific transgenic expression of lysyl oxidase-like protein-1 induces cardiac hypertrophy in mice

Cited by 21 publications

References 31 publications

Cardiomyocyte calcineurin is required for the onset and progression of cardiac hypertrophy and fibrosis in adult mice

Cardiomyocyte calcineurin is required for the onset and progression of cardiac hypertrophy and fibrosis in adult mice

The Role of Lysyl Oxidase Enzymes in Cardiac Function and Remodeling

Matrix regulation of idiopathic pulmonary fibrosis: the role of enzymes

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