Detrimental role of lysyl oxidase in cardiac remodeling

Hajj, Elia C. El; Hajj, Milad C. El; Ninh, Van K.; Bradley, Jessica M.; Claudino, Mário A.; Gardner, Jason D.

doi:10.1016/j.yjmcc.2017.06.013

Cited by 25 publications

(21 citation statements)

References 61 publications

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“…Lox catalyzes collagen cross-linking. Inhibition of Lox with BAPN attenuates volume overload-induced pathological ECM remodeling in rat hearts 32 , 33 and in angiotensin II-induced vascular stiffness in mice 34 . Administration of BAPN post-TAC surgery suppressed LVH and fibrosis of Kdm3a -Tg mice to the WT TAC level, including cardiac function and gravimetric measurements (Supplementary Fig.…”

Section: Resultsmentioning

confidence: 99%

Histone lysine dimethyl-demethylase KDM3A controls pathological cardiac hypertrophy and fibrosis

et al. 2018

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Left ventricular hypertrophy (LVH) is a major risk factor for cardiovascular morbidity and mortality. Pathological LVH engages transcriptional programs including reactivation of canonical fetal genes and those inducing fibrosis. Histone lysine demethylases (KDMs) are emerging regulators of transcriptional reprogramming in cancer, though their potential role in abnormal heart growth and fibrosis remains little understood. Here, we investigate gain and loss of function of an H3K9me2 specific demethylase, Kdm3a, and show it promotes LVH and fibrosis in response to pressure-overload. Cardiomyocyte KDM3A activates Timp1 transcription with pro-fibrotic activity. By contrast, a pan-KDM inhibitor, JIB-04, suppresses pressure overload-induced LVH and fibrosis. JIB-04 inhibits KDM3A and suppresses the transcription of fibrotic genes that overlap with genes downregulated in Kdm3a-KO mice versus WT controls. Our study provides genetic and biochemical evidence for a pro-hypertrophic function of KDM3A and proof-of principle for pharmacological targeting of KDMs as an effective strategy to counter LVH and pathological fibrosis.

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Section: Resultsmentioning

confidence: 99%

Histone lysine dimethyl-demethylase KDM3A controls pathological cardiac hypertrophy and fibrosis

et al. 2018

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“…This anti-fibrotic effect of BAPN is in line with data from several in vivo studies. For example, BAPN treatment was found to reduce left ventricular stiffness and collagen content in a volume overload rat model [74,75], to diminish the extent of cardiac fibrosis in rats subjected to a high fat diet [76], and to attenuated cardiac fibrosis and ventricular dilatation in a murine myocardial infarction model [77].…”

Section: Discussionmentioning

confidence: 99%

Inhibition of Rho-associated kinases suppresses cardiac myofibroblast function in engineered connective and heart muscle tissues

Santos

Hartmann

Zimmermann

et al. 2019

Journal of Molecular and Cellular Cardiology

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Cardiac fibrosis is a hallmark of heart failure for which there is no effective pharmacological therapy. By genetic modification and in vivo inhibitor approaches it was suggested that the Rho-associated kinases (ROCK1 and ROCK2) are involved in pro-fibrotic signalling in cardiac fibroblasts and that they may serve as targets for anti-fibrotic therapies. We demonstrate that simultaneous inhibition of ROCK1 and ROCK2 strongly interfered with tissue formation and their biomechanical properties in a model of engineered connective tissue (ECT), comprised of cardiac fibroblasts and collagen. These effects were observed with both rat and human ECT. Inhibitors of different chemistries, including the isoquinoline inhibitors Fasudil and H1152P as well as the pyrazol-phenyl inhibitor SR-3677, showed comparable effects. By combined treatment of ECT with TGF-β and H1152P, we could identify ROCK as a mediator of TGF-β-dependent tissue stiffening. Moreover, expression analyses suggested that lysyl oxidase (LOX) is a downstream target of the ROCK-actin-MRTF/SRF pathway and inhibition of this pathway by Latrunculin A and CCG-203971 showed similar anti-fibrotic effects in the ECT model as ROCK inhibitors. In line with the collagen crosslinking function of LOX, its inhibition by βaminopropionitrile resulted in reduced ECT stiffness, but let tissue compaction unaffected. Finally, we show that ROCK inhibition also reduced the compaction and stiffness of engineered heart muscle tissues. Our results indicate that pharmacological inhibition of ROCK has a strong anti-fibrotic potential which is in part due to a decrease in the expression of the collagen crosslinking enzyme lysyl oxidase.

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“…The inhibition of LOX by BAPN modulated TGF-β signaling and collagen synthesis, but also the degree of macrophage infiltration [58]. In the rat model of aortocaval fistula-induced volume overload (VO), the expression and activity of LOX, as well as collagen and CCL, were progressively upregulated in parallel with an enhanced ventricular mass [59]. Interestingly, in this model, LOX activity negatively correlated with cardiac function, while LOX inhibition by BAPN completely circumvented the increase in fibrotic mediators, such as collagens, MMPs and their tissue inhibitors, and ameliorated the cardiac dysfunction caused by VO [60,61].…”

Section: Lox and Loxls In Dilated And Hypertrophic Cardiomyopathies Amentioning

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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Detrimental role of lysyl oxidase in cardiac remodeling

Cited by 25 publications

References 61 publications

Histone lysine dimethyl-demethylase KDM3A controls pathological cardiac hypertrophy and fibrosis

Histone lysine dimethyl-demethylase KDM3A controls pathological cardiac hypertrophy and fibrosis

Inhibition of Rho-associated kinases suppresses cardiac myofibroblast function in engineered connective and heart muscle tissues

The Role of Lysyl Oxidase Enzymes in Cardiac Function and Remodeling

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