Cross-linking versus RAGE: How do high molecular weight advanced glycation products induce cardiac dysfunction?

Deluyker, Dorien; Ferferieva, Vesselina; Noben, Jean-Paul; Swennen, Quirine; Bronckaers, Annelies; Lambrichts, Ivo; Rigo, Jean-Michel; Bito, Virginie

doi:10.1016/j.ijcard.2016.02.095

Cited by 34 publications

(45 citation statements)

References 47 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…However, in our experiments, application of HMW-AGEs for 4 min did not activate pJNK, suggesting a direct mechanism on cardiomyocytes and Ca 2+ channels rather than RAGE-mediated deleterious mechanisms. This result is also in accordance with what was previously reported on the mechanism of action of HMW-AGEs in vivo, in a chronic setting (Deluyker et al, 2016).…”

Section: Western Blotsupporting

confidence: 93%

Acute exposure to glycated proteins reduces cardiomyocyte contractile capacity

Deluyker

Evens

Beliën

et al. 2019

Experimental Physiology

Self Cite

View full text Add to dashboard Cite

New Findings What is the central question of this study?Does acute exposure to high molecular weight advanced glycation end products (HMW‐AGEs) alter cardiomyocyte contractile function? What is the main finding and its importance?Ventricular cardiomyocytes display reduced Ca2+ influx, resulting in reduced contractile capacity, after acute exposure to HMW‐AGEs, independent of activation of their receptor. Given that HMW‐AGEs are abundantly present in our Western diet, a better understanding of underlying mechanisms, especially in patients already displaying altered cardiac function, should be gained for these compounds. Abstract Sustained elevated levels of high molecular weight advanced glycation end products (HMW‐AGEs) are known to promote cardiac dysfunction. Recent data suggest that acutely elevated levels of AGEs occur in situations of increased oxidative stress. Whether this increase might have detrimental effects on cardiac function remains unknown. In this study, we investigated whether acute exposure to HMW‐AGEs affects cardiomyocyte function via activation of their receptor (RAGE) signalling pathway. Single cardiomyocytes from the left ventricle of adult male rats were obtained by enzymatic dissociation through retrograde perfusion of the aorta. Functional experiments were performed in cardiomyocytes pre‐incubated with or without an anti‐RAGE antibody. Unloaded cell shortening and L‐type Ca2+ current amplitude were evaluated in the presence or absence of HMW‐AGEs (200 μg ml−1). Expression of RAGE, c‐Jun N‐terminal kinase (JNK) and phosphorylated JNK (pJNK) were assessed by western blot. Experiments were performed at room temperature. After 4 min application of HMW‐AGEs, unloaded cell shortening was significantly reduced. This impaired contractile function was related to reduced Ca2+ influx. These alterations were also observed in cardiomyocytes pre‐incubated with anti‐RAGE antibody. Our study demonstrates that acute exposure to elevated levels of HMW‐AGEs leads to direct and irreversible cardiomyocyte dysfunction, independent of RAGE activation.

show abstract

Section: Western Blotsupporting

confidence: 93%

Acute exposure to glycated proteins reduces cardiomyocyte contractile capacity

Deluyker

Evens

Beliën

et al. 2019

Experimental Physiology

Self Cite

View full text Add to dashboard Cite

show abstract

“…In our study, we show that indeed, a decrease in LOX protein level correlates with the improved tau measured in vivo . These data are also in agreement with studies conducted in chronic HF patients as well as in rats with diastolic dysfunction demonstrating a direct correlation between collagen cross-linking and cardiac stiffness 34 , 36 . Accordingly, we also show that total interstitial collagen is increased in both the peri-infarct and remote area 33 , 34 .…”

Section: Discussionsupporting

confidence: 91%

“…As described previously 6 , transthoracic echocardiography parameters were assessed 8 weeks post-surgery with a Vivid i ultrasound machine (GE Vingmed Ultrasound) using a 10 MHz linear array transducer under 2% isoflurane anesthesia. A standard parasternal long axis image and short-axis views at mid-ventricular level were acquired at a temporal resolution of ≈ 200 frames per second.…”

Section: Methodsmentioning

confidence: 99%

“…Recently, we have demonstrated that a marked elevation in circulating AGEs levels in healthy rats occurs independently of circulating glucose levels. In that setting, animals exhibit diastolic dysfunction with increased cardiac stiffness and collagen deposition 6 . Recent studies corroborate the involvement of AGEs in other pathological conditions than diabetes, such as ischemia-reperfusion, enhanced states of oxidative stress and MI 7 , 8 .…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Pyridoxamine improves survival and limits cardiac dysfunction after MI

Deluyker

Ferferieva

Driesen

et al. 2017

Sci Rep

Self Cite

View full text Add to dashboard Cite

Advanced glycation end products (AGEs) play a key role in the progression of heart failure. Whether treatments limiting AGEs formation would prevent adverse left ventricular remodeling after myocardial infarction (MI) remain unknown. We investigated whether pyridoxamine (PM) could limit adverse cardiac outcome in MI. Rats were divided into MI, MI + PM and Sham. Echocardiography and hemodynamic parameters were used to assess cardiac function 8 weeks post-surgery. Total interstitial collagen, collagen I and collagen III were quantified using Sirius Red and polarized light microscopy. PM improved survival following LAD occlusion. Pre-treatment with PM significantly decreased the plasma AGEs levels. MI rats treated with PM displayed reduced left ventricular end-diastolic pressure and tau compared to untreated MI rats. Deformation parameters were also improved with PM. The preserved diastolic function was related to the reduced collagen content, in particular in the highly cross-linked collagen type I, mainly in the peri-infarct region, although not via TGF-β1 pathway. Our data indicate that PM treatment prevents the increase in AGEs levels and reduces collagen levels in a rat model of MI, resulting in an improved cardiac phenotype. As such, therapies targeting formation of AGEs might be beneficial in the prevention and/or treatment of maladaptive remodeling following MI.

show abstract

“…In particular, experiments in null mice evidence that the control of myocardial Lox expression depends on TRAF3 Interacting Protein 2 (TRAF3IP2), a redox-sensitive adaptor molecule and a decisive signaling intermediate in aldosterone/salt-induced cardiac hypertrophy and fibrosis [81]. Likewise, in rats, the hypertrophic and profibrotic cardiac effects of high molecular weight advanced glycation end products (HMW-AGEs) were likely due to the increase of LOX expression and the LOX-mediated CCL, which might be responsible for the higher cardiac stiffness promoted by these compounds [82]. Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a severe disease featured by an extensive fibrotic replacement.…”

Section: Lox In Other Pathophysiological Settings Leading To Cardiacmentioning

confidence: 99%

The Role of Lysyl Oxidase Enzymes in Cardiac Function and Remodeling

Rodrı́guez

Martínez-González

2019

Cells

View full text Add to dashboard Cite

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...

show abstract

Cross-linking versus RAGE: How do high molecular weight advanced glycation products induce cardiac dysfunction?

Cited by 34 publications

References 47 publications

Acute exposure to glycated proteins reduces cardiomyocyte contractile capacity

Acute exposure to glycated proteins reduces cardiomyocyte contractile capacity

Pyridoxamine improves survival and limits cardiac dysfunction after MI

The Role of Lysyl Oxidase Enzymes in Cardiac Function and Remodeling

Contact Info

Product

Resources

About