Search

Oxidized low-density lipoprotein (oxLDL) is associated with cardiac damage and causes injury to multiple cell types. We aimed to investigate the role of oxLDL in ventricular stress. We first examined the association between circulating oxLDL and N-terminal pro-brain natriuretic peptide (NT-proBNP), a marker of myocardial stress, in young subjects (30-50 years) with or without stable coronary artery disease (SCAD). oxLDL and NT-proBNP were significantly higher in subjects at high cardiovascular risk (CVR) than in subjects at low CVR and were associated independently of traditional CVR factors and C-reactive protein. Furthermore, the levels of oxLDL and NT-proBNP were significantly lower in subjects with SCAD than in peers at high CVR. To determine the intracellular mechanisms involved in the cardiac effects of oxLDL, we analyzed the in vitro effect of oxLDL on intracellular Ca 2+ handling in adult rat ventricular cardiomyocytes using confocal microscopy. Acute challenge of adult ventricular cardiomyocytes to oxLDL reduced systolic Ca 2+ transients and sarcoplasmic reticulum Ca 2+ load. Moreover, diastolic spontaneous Ca 2+ leak increased significantly after acute exposure to oxLDL. Thus, we demonstrate that oxLDL associates with NT-proBNP in young subjects, and can directly induce Ca 2+ mishandling in adult ventricular cardiomyoyctes, predisposing cardiomyocytes to cardiac dysfunction and arrhythmogenicity.

Background and Purpose: Klotho is a membrane-bound or soluble protein, originally identified as an age-suppressing factor and regulator of mineral metabolism. Klotho deficiency is associated with the development of renal disease, but its role in cardiac function in the context of uraemic cardiomyopathy is unknown., Experimental Approach: We explored the effects of Klotho on cardiac Ca 2+ cycling. We analysed Ca 2+ handling in adult cardiomyocytes from Klotho-deficient (kl/kl) mice and from a murine model of 5/6 nephrectomy (Nfx). We also studied the effect of exogenous Klotho supplementation, by chronic recombinant Klotho treatment, or endogenous Klotho overexpression, using transgenic mice overexpressing Klotho (Tg-Kl), on uraemic cardiomyopathy. Hearts from Nfx mice were used to study Ca 2+ sensitivity of ryanodine receptors and their phosphorylation state., Key Results: Cardiomyocytes from kl/kl mice showed decreased amplitude of intracellular Ca 2+ transients and cellular shortening together with an increase in pro-arrhythmic Ca 2+ events compared with cells from wild-type mice. Cardiomyocytes from Nfx mice exhibited the same impairment in Ca 2+ cycling as kl/kl mice. Changes in Nfx cardiomyocytes were explained by higher sensitivity of ryanodine receptors to Ca 2+ and their increased phosphorylation at the calmodulin kinase type II and protein kinase A sites. Ca 2+ mishandling in Nfx-treated mice was fully prevented by chronic recombinant Klotho administration or transgenic Klotho overexpression., Conclusions and Implications: Klotho emerges as an attractive therapeutic tool to improve cardiac Ca 2+ mishandling observed in uraemic cardiomyopathy. Strategies that improve Klotho availability are good candidates to protect the heart from functional cardiac alterations in renal disease., (© 2020 The British Pharmacological Society.)

Renal replacement therapy (RRT) is complicated by a chronic state of inflammation and a high mortality risk. However, different RRT modalities can have a selective impact on markers of inflammation and oxidative stress. We evaluated the levels of active matrix metalloproteinase (MMP)-9 in patients undergoing two types of dialysis (high-flux dialysis (HFD) and on-line hemodiafiltration (OL-HDF)) and in kidney transplantation (KT) recipients. Active MMP-9 was measured by zymography and ELISA before (pre-) and after (post-) one dialysis session, and at baseline and follow-up (7 and 14 days, and 1, 3, 6, and 12 months) after KT. Active MMP-9 decreased post-dialysis only in HFD patients, while the levels in OL-HDF patients were already lower before dialysis. Active MMP-9 increased at 7 and 14 days post-KT and was restored to baseline levels three months post-KT, coinciding with an improvement in renal function and plasma creatinine. Active MMP-9 correlated with pulse pressure as an indicator of arterial stiffness both in dialysis patients and KT recipients. In conclusion, active MMP-9 is better controlled in OL-HDF than in HFD and is restored to baseline levels along with stabilization of renal parameters after KT. Active MMP-9 might act as a biomarker of arterial stiffness in RRT., Competing Interests: The authors declare no conflicts of interest.

Hemodialysis patients experience high oxidative stress because of systemic inflammation and depletion of antioxidants. Little is known about the global oxidative status during dialysis or whether it is linked to the type of dialysis. We investigated the oxidative status before (pre-) and after (post-) one dialysis session in patients subjected to high-flux dialysis (HFD) or on-line hemodiafiltration (OL-HDF). We analyzed carbonyls, oxidized LDL (oxLDL), 8-hydroxy-2'-deoxyguanosine, and xanthine oxidase (XOD) activity as oxidative markers, and total antioxidant capacity (TAC), catalase, and superoxide dismutase activities as measures of antioxidant defense. Indices of oxidative damage (OxyScore) and antioxidant defense (AntioxyScore) were computed and combined into a global DialysisOxyScore. Both dialysis modalities cleared all markers ( p < 0.01) except carbonyls, which were unchanged, and oxLDL, which increased post-dialysis ( p < 0.01). OxyScore increased post-dialysis ( p < 0.001), whereas AntioxyScore decreased ( p < 0.001). XOD and catalase activities decreased post-dialysis after OL-HDF ( p < 0.01), and catalase activity was higher after OL-HDF than after HFD ( p < 0.05). TAC decreased in both dialysis modalities ( p < 0.01), but remained higher in OL-HDF than in HFD post-dialysis ( p < 0.05), resulting in a lower overall DialysisOxyScore ( p < 0.05). Thus, patients on OL-HDF maintain higher levels of antioxidant defense, which might balance the elevated oxidative stress during dialysis, although further longitudinal studies are needed.

Background: Cardiac dysfunction and arrhythmia are common and onerous cardiovascular events in end-stage renal disease (ESRD) patients, especially those on dialysis. Fibroblast growth factor (FGF)-23 is a phosphate-regulating hormone whose levels dramatically increase as renal function declines. Beyond its role in phosphorus homeostasis, FGF-23 may elicit a direct effect on the heart. Whether FGF-23 modulates ventricular cardiac rhythm is unknown, prompting us to study its role on excitation-contraction (EC) coupling., Methods: We examined FGF-23 in vitro actions on EC coupling in adult rat native ventricular cardiomyocytes using patch clamp and confocal microscopy and in vivo actions on cardiac rhythm using electrocardiogram., Results: Compared with vehicle treatment, FGF-23 induced a significant decrease in rat cardiomyocyte contraction, L-type Ca2+ current, systolic Ca2+ transients and sarcoplasmic reticulum (SR) load and SR Ca2+-adenosine triphosphatase 2a pump activity. FGF-23 induced pro-arrhythmogenic activity in vitro and in vivo as automatic cardiomyocyte extracontractions and premature ventricular contractions. Diastolic spontaneous Ca2+ leak (sparks and waves) was significantly increased by FGF-23 via the calmodulin kinase type II (CaMKII)-dependent pathway related to hyperphosphorylation of ryanodine receptors at the CaMKII site Ser2814. Both contraction dysfunction and spontaneous pro-arrhythmic Ca2+ events induced by FGF-23 were blocked by soluble Klotho (sKlotho)., Conclusions: Our results show that FGF-23 reduces contractility and enhances arrhythmogenicity through intracellular Ca2+ mishandling. Blocking its actions on the heart by improving sKlotho bioavailability may enhance cardiac function and reduce arrhythmic events frequently observed in ESRD., (© The Author(s) 2019. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.)

Background and Objective: Matrix metalloproteinases (MMPs) are involved in deleterious tissue remodeling associated with target organ damage in renal disease. The aim of this study was to study the association between renal dysfunction and activity of the inflammatory metalloproteinase MMP-9 in hypertensive patients with mild-moderate chronic kidney disease (CKD)., Material and Methods: Plasmatic active MMP-9, total MMP-9, tissue inhibitor of MMP-9 (TIMP-1), MMP-9/TIMP-1 ratio and MMP-9-TIMP-1 interaction were analyzed in 37 hypertensive patients distributed by estimated glomerular filtration rate (eGFR) in 3 groups:>90, 90-60 y 60-30mL/min/1.73 m 2 ., Results: Total MMP-9 was not different as eGFR declines. TIMP-1 was significantly increased in hypertensive patients with eGFR 60-30mL/min/1.73 m 2 (P<.01 versus>90mL/min/1.73 m 2 ). This relates to the significant decrease in the interaction between MMP-9-TIMP-1 observed in patients with eGFR 60-30mL/min/1.73 m 2 (P<.01 versus>90mL/min/1.73 m 2 ). Despite the systemic elevation of TIMP-1, active MMP-9 was significantly increased in hypertensive patients with eGFR 60-30mL/min/1.73 m 2 (P<.05 and P<0.01 versus>90 and 90-60mL/min/1.73 m 2 , respectively). TIMP-1, active MMP-9 and MMP-9-TIMP-1 interaction significantly correlate with the decline in renal function, which was not observed with total MMP-9., Conclusions: The progression of CKD, even in stages where the decline of renal function is still moderate, is associated with an increase in MMP-9 activity, which could be considered as a potential therapeutic target., (Copyright © 2018 Sociedad Española de Nefrología. Published by Elsevier España, S.L.U. All rights reserved.)