Regulation of adverse remodelling by osteopontin in a genetic heart failure model

Psarras, Stelios; Mavroidis, Manolis; Sanoudou, Despina; Davos, Constantinos H.; Xanthou, Georgina; Varela, Aimilia; Panoutsakopoulou, Vily; Capetanaki, Yassemi

doi:10.1093/eurheartj/ehr119

Cited by 83 publications

(105 citation statements)

References 43 publications

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“…In agreement with its cardioprotective efficacy, treatment with RG prevented LV interstitial collagen deposition at a protein level (as indicated by immunofluorescence staining and HOP assay) and less cardiomyocyte degeneration was made evident by desmin staining21 in the BZ. We also found that collagen type I mRNA levels were significantly increased in the BZ of the RG group.…”

Section: Discussionsupporting

confidence: 68%

The neuroprotective agent Rasagiline mesylate attenuates cardiac remodeling after experimental myocardial infarction

Varela¹,

Mavroidis

Katsimpoulas³

et al. 2017

ESC Heart Failure

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AimRasagiline mesylate (N‐propargyl‐1 (R)‐aminoindan) (RG) is a selective, potent irreversible inhibitor of monoamine oxidase‐B with cardioprotective and anti‐apoptotic properties. We investigated whether it could be cardioprotective in a rat model undergoing experimental myocardial infarction (MI) by permanent ligation of the left anterior descending coronary artery.Methods and resultsRG was administered, intraperitoneally, for 28 days (2 mg/kg) starting 24 h after MI induction. Echocardiography analysis revealed a significant reduction in left ventricular end‐systolic and diastolic dimensions and preserved fractional shortening in RG‐treated compared with normal saline group at 28 days post‐MI (31.6 ± 2.3 vs. 19.6 ± 1.8, P < 0.0001), respectively. Treatment with RG prevented tissue fibrosis as indicated by interstitial collagen estimation by immunofluorescence staining and hydroxyproline content and attenuated the number of apoptotic myocytes in the border zone (65%) as indicated by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay. Caspase 3 relative protein levels were significantly decreased in the non‐infarcted myocardium. Markedly decreased malondialdehyde levels in the border zone indicate a reduction in tissue oxidative stress.ConclusionsOur study demonstrates a positive effect of RG in the post‐MI period with a significant attenuation in cardiac remodelling.

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Section: Discussionsupporting

confidence: 68%

The neuroprotective agent Rasagiline mesylate attenuates cardiac remodeling after experimental myocardial infarction

Varela¹,

Mavroidis

Katsimpoulas³

et al. 2017

ESC Heart Failure

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“…Galectin-3 is expressed by activated macrophages and induces cardiac fibroblasts to proliferate and deposit type I collagen in the myocardium (1 ). The expression of galectin-3 is substantially upregulated in animal models of heart failure (HF) 4 and occurs before the development of overt clinical HF (1)(2)(3). The protein localizes to areas of fibrosis, suggesting an active role in modulation of the extracellular matrix (1 ).…”

confidence: 99%

“…Mediators such as osteopontin stimulate these macrophages to secrete galectin-3 (3 ), which appears to act through upregulation of the transforming growth factor (TGF)-␤/ Smad3 signaling pathway, causing cardiac fibroblasts to proliferate and produce type I collagen, ultimately leading to an accumulation of myocardial collagen and impaired diastolic and systolic function (1,4 ). In a mouse model of desmin-deficient HF, knocking out the gene for osteopontin resulted in dramatically decreased galectin-3 expression and subsequently less cardiac fibrosis and improved echocardiographic parameters of ventricular function (3 ). In patients with chronic HF, galectin-3 concentrations have been correlated with markers of extracellular matrix turnover, such as type III amino-terminal propeptide of procol- lagen (PIIINP) and matrix metalloproteinase 2 (MMP-2), implying a relationship between macrophage activation and collagen turnover (18 ).…”

Section: Galectin-3 and The Pathobiology Of Hfmentioning

confidence: 99%

Galectin-3 and the Development of Heart Failure after Acute Coronary Syndrome: Pilot Experience from PROVE IT-TIMI 22

et al. 2012

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BACKGROUND Galectin-3 is a β-galactoside–binding lectin that has been implicated in cardiac fibrosis and remodeling, is increased in models of failure-prone hearts, and has prognostic value in patients with heart failure (HF). The relationship between galectin-3 and the development of HF after acute coronary syndrome (ACS) is unknown. METHODS In a nested case-control study among patients with ACS in PROVE IT-TIMI 22, we identified 100 cases with a hospitalization for new or worsening HF. Controls were matched (1:1) for age, sex, ACS type, and randomized treatment. Serum galectin-3 was measured at baseline (within 7 days post-ACS). RESULTS Patients who developed HF had higher baseline galectin-3 [median 16.7 μg/L (25th, 75th percentile 14.0, 20.6) vs 14.6 μg/L (12.0, 17.6), P = 0.004]. Patients with baseline galectin-3 above the median had an odds ratio of 2.1 (95% CI 1.2–3.6) for developing HF, P = 0.010. Galectin-3 showed a graded relationship with risk of HF. Cases were more likely to have hypertension, diabetes, prior MI, and prior HF; after adjustment for these factors, this graded relationship with galectin-3 quartile and HF remained significant [adjusted OR 1.4 (95% CI 1.1–1.9), P = 0.020]. When BNP was added to the model, the relationship between galectin-3 and HF was attenuated [adjusted OR 1.3 (95% CI: 0.96–1.9), P = 0.08]. CONCLUSIONS The finding that galectin-3 is associated with the risk of developing HF following ACS adds to emerging evidence supporting galectin-3 as a biomarker of adverse remodeling contributing to HF as well as a potential therapeutic target.

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“…Mice deficient for desmin develop both skeletal and myocardial defects that are strongly linked to impaired mitochondrial morphology and function (Milner et al, 1996(Milner et al, , 1999(Milner et al, , 2000Li et al, 1996;Papathanasiou et al, 2015). These mitochondrial abnormalities lead to cardiomyocyte death and myocardial degeneration, accompanied by inflammation and fibrosis, resulting in dilated cardiomyopathy (DCM) and heart failure (Milner et al, 2000;Mavroidis and Capetanaki 2002;Capetanaki et al, 2007;Psarras et al, 2012;Mavroidis et al, 2015). In humans, over 70 desmin mutations have been linked to desmin-related cardiomyopathies, of which DCM is the most frequent van Spaendonck-Zwarts et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

Desmin and αB-crystallin interplay in maintenance of mitochondrial homeostasis and cardiomyocyte survival

Diokmetzidou

Soumaka

Kloukina

et al. 2016

Journal of Cell Science

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The association of desmin with the α-crystallin Β-chain (αΒ-crystallin; encoded by CRYAB), and the fact that mutations in either one of them leads to heart failure in humans and mice, suggests a potential compensatory interplay between the two in cardioprotection. To address this hypothesis, we investigated the consequences of αΒ-crystallin overexpression in the desmin-deficient (Des) mouse model, which possesses a combination of the pathologies found in most cardiomyopathies, with mitochondrial defects as a hallmark. We demonstrated that cardiac-specific αΒ-crystallin overexpression ameliorates all these defects and improves cardiac function to almost wild-type levels. Protection by αΒ-crystallin overexpression is linked to maintenance of proper mitochondrial protein levels, inhibition of abnormal mitochondrial permeability transition pore activation and maintenance of mitochondrial membrane potential (Δψ m ). Furthermore, we found that both desmin and αΒ-crystallin are localized at sarcoplasmic reticulum (SR)-mitochondria-associated membranes (MAMs), where they interact with VDAC, Mic60 -the core component of mitochondrial contact site and cristae organizing system (MICOS) complex -and ATP synthase, suggesting that these associations could be crucial in mitoprotection at different levels.

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Regulation of adverse remodelling by osteopontin in a genetic heart failure model

Cited by 83 publications

References 43 publications

The neuroprotective agent Rasagiline mesylate attenuates cardiac remodeling after experimental myocardial infarction

The neuroprotective agent Rasagiline mesylate attenuates cardiac remodeling after experimental myocardial infarction

Galectin-3 and the Development of Heart Failure after Acute Coronary Syndrome: Pilot Experience from PROVE IT-TIMI 22

Desmin and αB-crystallin interplay in maintenance of mitochondrial homeostasis and cardiomyocyte survival

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