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Electron micrographs showing severe vacuolar degeneration in a cardiomyocyte from an untreated UM-X7.1 heart. Note that the cytoplasm is almost entirely replaced by vacuoles. Arrows indicate the few remaining myofibrils. Nucl, nucleus. *, a neighboring cardiomyocyte. Bar, 1 µm. Reprinted from Miyata et al., Am J Pathol 2006; 168:386-97 with permission from the American Society for Investigative Pathology.
Source publication
Numerous cardiomyocytes were found to show autophagic vacuolar degeneration in the UM-X7.1 hamster model of human dilated cardiomyopathy, and autophagy-related proteins--i.e., ubiquitin, cathepsin D and Rab7--were upregulated in those hearts. Importantly, Evans blue-positive cardiomyocytes with leaky plasma membranes were also positive for cathepsi...
Context in source publication
Context 1
... of cathepsin D in Evans blue dye-positive cardiomyocytes with leaky plasma membranes. 6 Cardiomyocyte death occurs via several pathways in heart failure and is thought to be responsible for its development and progression ( Fig. 1). We have observed cardiomyocytes in which the cytoplasm has been replaced almost entirely with autophagic vacuoles (Fig. 2). Sarcomeres-i.e., the contractile apparatus-remained only at the very edge of these cells. It is highly plausible that, even if not dead, cardiomyocytes with such severe degenerative changes cannot produce meaningful amounts of contractile power and thus contribute to a worsening of cardiac function, which prompts us to consider the ...
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Citations
... In eukaryotic species, autophagy is a crucial process for recycling intracellular components. More and more research confirms that autophagy is activated in numerous cardiovascular pathogenic conditions, such as myocardial hypertrophy [21], heart failure [22], atherosclerosis [23], and myocardial I/R injury [24]. Emerging investigations in recent years have confirmed the significance of autophagy in MIRI. ...
Background
The purpose of this research was to verify that vericiguat, a soluble guanylate cyclase (sGC) stimulator, reduces myocardial ischemic reperfusion injury (MIRI), and to learn how this reduction happens.
Methods and results
To develop an ischaemia/reperfusion (I/R) model, the left anterior descending artery was blocked in minipigs under anesthesia for 90 minutes, followed by 180 minutes of reperfusion. Vericiguat is administered three hours before surgery. Two weeks after receiving therapy, pigs underwent cardiovascular magnetic resonance imaging (MRI) to evaluate the results. The MRI results suggest improvement in the myocardial infarct after vericiguat treatment. Vericiguat treatment for two weeks enhanced vascularity, inhibited pro-inflammatory cells, and decreased collagen deposition in the infarct zone of pigs. Short-term experiments investigating possible explanations have indicated that vericiguat has antiapoptotic effects on cardiomyocytes and increases levels of autophagy.
Conclusions
Vericiguat, an SGC activator, reduces MIRI in pigs by boosting autophagy, preventing apoptosis, and promoting angiogenesis.
... 2,3 Cellular autophagy or autophagocytosis is the self-cannibalization mechanism of cells with which the selective removal of damaged cytoplasmic components takes place. Autophagy is involved in maintaining cardiac function; however, autophagy is hyperactivated in pathological conditions, including heart failure, 4 cardiac hypertrophy, 5 ischaemic cardiomyopathy, 6 and cardiac senescence. 7 Especially in the pathogenesis of diabetic cardiomyopathy, excessive and de-regulated autophagy appears to play a key role. ...
Background and aims:
Sodium-glucose cotransporter 2 (SGLT2) inhibitors have beneficial effects on heart failure and cardiovascular mortality in diabetic and nondiabetic patients, with unclear mechanisms. Autophagy is a cardioprotective mechanism under acute stress conditions, but excessive autophagy accelerates myocardial cell death leading to autosis. We evaluated the protective role of empagliflozin (EMPA) against cardiac injury in murine diabetic cardiomyopathy.
Methods and results:
Male mice, rendered diabetics by one single intraperitoneal injection of streptozotocin and treated with EMPA (30 mg/kg/day) had fewer apoptotic cells (4.9 ± 2.1 vs 1 ± 0.5 TUNEL-positive cells %, p < 0.05), less senescence (10.1 ± 2 vs 7.9 ± 1.2 β-gal positivity/tissue area, p < 0.05), fibrosis (0.2 ± 0.05 vs 0.15 ± 0.06, p < 0.05 fibrotic area/tissue area), autophagy (7.9 ± 0.05 vs 2.3 ± 0.6 fluorescence intensity/total area, p < 0.01), and connexin (Cx)-43 lateralization compared with diabetic mice. Proteomic analysis showed a downregulation of the 5' adenosine monophosphate-activated protein kinase (AMPK) pathway and upstream activation of sirtuins in the heart of diabetic mice treated with EMPA compared with diabetic mice. Because sirtuin activation leads to modulation of cardiomyogenic transcription factors, we analyzed the DNA binding activity to serum response elements (SRE) of serum response factor (SRF) by electromobility shift assay. Compared with diabetic mice (0.5 ± 0.01 densitometric units, DU), nondiabetic mice treated with EMPA (2.2 ± 0.01 DU, p < 0.01) and diabetic mice treated with EMPA (2.0 ± 0.1 DU, p < 0.01) significantly increased SRF binding activity to SRE, paralleled by increased cardiac actin expression (4.1 ± 0.1 vs 2.2 ± 0.01 target protein/β-actin ratio, p < 0.01). EMPA significantly reversed cardiac dysfunction on echocardiography in diabetic mice and inhibited excessive autophagy in high-glucose-treated cardiomyocytes by inhibiting the autophagy inducer GSK3β, leading to reactivation of cardiomyogenic transcription factors.
Conclusions:
Taken together, our results describe a novel paradigm in which EMPA inhibits hyperactivation of autophagy through the AMPK/GSK3β signaling pathway in the context of diabetes.
... Since the heart has cardiomyocytes that are terminally differentiated non-dividing cells, the correct function of the autophagic degradation process is essential for the maintenance of myocyte homeostasis (Cuervo 2004). Though autophagy is generally viewed as a survival mechanism, excessive autophagy has been associated with cardiac disease, including ischemia/reperfusion, cardiac oxidative stress, and heart failure (Hariharan et al. 2011;Takemura et al. 2006;Valentim et al. 2006). In human failing hearts, both apoptosis and massive autophagy were detected (Kostin et al. 2003). ...
Mitoxantrone (MTX) is an antineoplastic agent used to treat advanced breast cancer, prostate cancer, acute leukemia, lymphoma and multiple sclerosis. Although it is known to cause cumulative dose-related cardiotoxicity, the underlying mechanisms are still poorly understood. This study aims to compare the cardiotoxicity of MTX and its’ pharmacologically active metabolite naphthoquinoxaline (NAPHT) in an in vitro cardiac model, human-differentiated AC16 cells, and determine the role of metabolism in the cardiotoxic effects. Concentration-dependent cytotoxicity was observed after MTX exposure, affecting mitochondrial function and lysosome uptake. On the other hand, the metabolite NAPHT only caused concentration-dependent cytotoxicity in the MTT reduction assay. When assessing the effect of different inhibitors/inducers of metabolism, it was observed that metyrapone (a cytochrome P450 inhibitor) and phenobarbital (a cytochrome P450 inducer) slightly increased MTX cytotoxicity, while 1-aminobenzotriazole (a suicide cytochrome P450 inhibitor) decreased fairly the MTX-triggered cytotoxicity in differentiated AC16 cells. When focusing in autophagy, the mTOR inhibitor rapamycin and the autophagy inhibitor 3-methyladenine exacerbated the cytotoxicity caused by MTX and NAPHT, while the autophagy blocker, chloroquine, partially reduced the cytotoxicity of MTX. In addition, we observed a decrease in p62, beclin-1, and ATG5 levels and an increase in LC3-II levels in MTX-incubated cells. In conclusion, in our in vitro model, neither metabolism nor exogenously given NAPHT are major contributors to MTX toxicity as seen by the residual influence of metabolism modulators used on the observed cytotoxicity and by NAPHT’s low cytotoxicity profile. Conversely, autophagy is involved in MTX-induced cytotoxicity and MTX seems to act as an autophagy inducer, possibly through p62/LC3-II involvement.
Graphical abstract
... Autophagy is essential for maintaining a normal homeostatic function in cardiac cells via a continual process of removing, repairing, and replacing damaged cellular materials. It also plays an important role in cardiovascular pathologies and several studies have documented autophagy disturbances in many cardiac disease states, including heart failure, cardiac hypertrophy, pressure-overload heart failure, ischemic heart disease, and cardiomyopathies [52,[87][88][89][90][91][92][93][94][95]. Increased autophagy during ischemia was found in a mouse model and this increase was considered as a beneficial response leading to the elimination of oxidized and damaged cellular components [96]. ...
Reactive oxygen and nitrogen species produced at low levels under normal cellular metabolism act as important signal molecules. However, at increased production, they cause damage associated with oxidative stress, which can lead to the development of many diseases, such as cardiovascular, metabolic, neurodegenerative, diabetes, and cancer. The defense systems used to maintain normal redox homeostasis plays an important role in cellular responses to oxidative stress. The key players here are Nrf2-regulated redox signaling and autophagy. A tight interface has been described between these two processes under stress conditions and their role in oxidative stress-induced diseases progression. In this review, we focus on the role of Nrf2 as a key player in redox regulation in cell response to oxidative stress. We also summarize the current knowledge about the autophagy regulation and the role of redox signaling in this process. In line with the focus of our review, we describe in more detail information about the interplay between Nrf2 and autophagy pathways in myocardium and the role of these processes in cardiovascular disease development.
... Correlation analysis revealed a decrease in the number of immature CMCs with age, indicating an increasing differentiation of the myocardium. Signs of dystrophic changes in the CMCs ultrastructure and autophagy (myelin-like membrane structures, phagosomes) in the myocardium of children with TF were rarely observed, although these substructures are described in CMCs in various forms of cardiovascular pathology [89][90][91][92][93][94][95][96][97][98][99]. They are considered as markers of insufficient CMCs adaptation to hemodynamic overload and hypoxemia. ...
The myocardium of children with tetralogy of Fallot (TF) undergoes hemodynamic overload and hypoxemia immediately after birth. Comparative analysis of changes in the ploidy and morphology of the right ventricular cardiomyocytes in children with TF in the first years of life demonstrated their significant increase compared with the control group. In children with TF, there was a predominantly diffuse distribution of Connexin43-containing gap junctions over the cardiomyocytes sarcolemma, which redistributed into the intercalated discs as cardiomyocytes differentiation increased. The number of Ki67-positive cardiomyocytes varied greatly and amounted to 7.0–1025.5/106 cardiomyocytes and also were decreased with increased myocytes differentiation. Ultrastructural signs of immaturity and proliferative activity of cardiomyocytes in children with TF were demonstrated. The proportion of interstitial tissue did not differ significantly from the control group. The myocardium of children with TF under six months of age was most sensitive to hypoxemia, it was manifested by a delay in the intercalated discs and myofibril assembly and the appearance of ultrastructural signs of dystrophic changes in the cardiomyocytes. Thus, the acceleration of ontogenetic growth and differentiation of the cardiomyocytes, but not the reactivation of their proliferation, was an adaptation of the immature myocardium of children with TF to hemodynamic overload and hypoxemia.
... Heart failure caused by these diseases further promotes abnormal myocardial remodeling, which in turn exacerbates heart failure to form a vicious circle (8). Excessive fibrosis, degeneration and loss of cardiomyocytes have been involved in this pathological process (9)(10)(11). Although the potentially complex molecular regulatory networks have been extensively studied, our knowledge of pathological cardiac remodeling is still limited (12)(13)(14). ...
Background: Pathological tissue remodeling such as fibrosis is developed in various cardiac diseases. As one of cardiac activated-myofibroblast protein markers, CKAP4 may be involved in this process and the mechanisms have not been explored.
Methods: We assumed that CKAP4 held a role in the regulation of cardiac fibrotic remodeling as an RNA-binding protein. Using improved RNA immunoprecipitation and sequencing (iRIP-seq), we sought to analyze the RNAs bound by CKAP4 in normal atrial muscle (IP1 group) and remodeling fibrotic atrial muscle (IP2 group) from patients with cardiac valvular disease. Quantitative PCR and Western blotting were applied to identify CKAP4 mRNA and protein expression levels in human right atrium samples.
Results: iRIP-seq was successfully performed, CKAP4-bound RNAs were characterized. By statistically analyzing the distribution of binding peaks in various regions on the reference human genome, we found that the reads of IP samples were mainly distributed in the intergenic and intron regions implying that CKAP4 is more inclined to combine non-coding RNAs. There were 913 overlapping binding peaks between the IP1 and IP2 groups. The top five binding motifs were obtained by HOMER, in which GGGAU was the binding sequence that appeared simultaneously in both IP groups. Binding peak-related gene cluster enrichment analysis demonstrated these genes were mainly involved in biological processes such as signal transduction, protein phosphorylation, axonal guidance, and cell connection. The signal pathways ranking most varied in the IP2 group compared to the IP1 group were relating to mitotic cell cycle, protein ubiquitination and nerve growth factor receptors. More impressively, peak analysis revealed the lncRNA-binding features of CKAP4 in both IP groups. Furthermore, qPCR verified CKAP4 differentially bound lncRNAs including LINC00504, FLJ22447, RP11-326N17.2, and HELLPAR in remodeling myocardial tissues when compared with normal myocardial tissues. Finally, the expression of CKAP4 is down-regulated in human remodeling fibrotic atrium.
Conclusions: We reveal certain RNA-binding features of CKAP4 suggesting a relevant role as an unconventional RNA-binding protein in cardiac remodeling process. Deeper structural and functional analysis will be helpful to enrich the regulatory network of cardiac remodeling and to identify potential therapeutic targets.
... In parallel, activation of autophagy has been shown to prevent TAC-induced ventricular hypertrophy and improve ventricular function (Ha et al., 2005;McMullen et al., 2004). However, excessive autophagy induction in failing hearts could also lead to cardiomyocyte cell death Knaapen et al., 2001;Kostin et al., 2003;Takemura et al., 2006). Currently, the mechanosensors and cellular signaling pathways that control the regulation of stretch-or tension-induced autophagy are far from being well understood. ...
Physical constraints, such as compression, shear stress, stretching and tension, play major roles during development, tissue homeostasis, immune responses and pathologies. Cells and organelles also face mechanical forces during migration and extravasation, and investigations into how mechanical forces are translated into a wide panel of biological responses, including changes in cell morphology, membrane transport, metabolism, energy production and gene expression, is a flourishing field. Recent studies demonstrate the role of macroautophagy in the integration of physical constraints. The aim of this Review is to summarize and discuss our knowledge of the role of macroautophagy in controlling a large panel of cell responses, from morphological and metabolic changes, to inflammation and senescence, for the integration of mechanical forces. Moreover, wherever possible, we also discuss the cell surface molecules and structures that sense mechanical forces upstream of macroautophagy.
... It seems reasonable to suppose that a modest activation of autophagy is required to maintain cardiac function during the process of hypertrophy in hearts subjected to moderate pressure overload (PO). On the other hand, in PO-induced HF, an excessive induction of autophagy may trigger cardiomyocyte death in the failing heart [60]. Advanced glycation end products (RAGE) are involved in the progression of HF by upregulating autophagy. ...
Autophagy is a self-degradative pathway by which subcellular elements are broken down intracellularly to maintain cellular homeostasis. Cardiac autophagy commonly decreases with aging and is accompanied by the accumulation of misfolded proteins and dysfunctional organelles, which are undesirable to the cell. Reduction of autophagy over time leads to aging-related cardiac dysfunction and is inversely related to longevity. However, despite the increasing interest in autophagy in cardiac diseases and aging, the process remains an undervalued and disregarded object in calcific valvular disease. Neither the nature through which autophagy is triggered nor the interplay between autophagic machinery and targeted molecules during aortic valve calcification are fully understood. Recently, the upregulation of autophagy has been shown to result in cardioprotective effects against cell death as well as its origin. Here, we review the evidence that shows how autophagy can be both beneficial and detrimental as it pertains to aortic valve calcification in the heart.
... In diabetic cardiomyopathy, autophagy was found to be adapted in different ways (increased in type 1 diabetes but reduced in type 2 diabetes [14]). In failing hearts, autophagy was found to change in dynamic ways (suppressed in the initial stage, and activated in the endstage) [15,16]. These findings suggest the importance of autophagy. ...
... Studies have found that autophagy plays a role in the pathophysiology of HF. In pressure overload-induced cardiac remodelling, autophagy was suppressed in the compensation process and then activated in the decompensated process [15,16]. Studies have reported that many autophagy activators, such as rapamycin, metformin and 5-aminoimidazole 1 carboxamide ribonucleoside (AICAR), improve cardiac function, reduce cardiac hypertrophy, and delay the progress of HF during pressure overload [25][26][27]. ...
Introduction
Leucine-rich repetitive kinase-2 (LRRK2) is a Parkinson's disease-related gene that also participates in many inflammatory diseases. However, the functional role of LRRK2 in cardiovascular disease is not clear.
Objective
In this study, we aimed to elucidate the role of LRRK2 in cardiac remodelling under pressure overload.
Methods
Aortic banding surgery was performed to induce cardiac remodelling in a LRRK2 knockout mouse model. A cardiomyocyte remodelling model was established by phenylephrine (PE) stimulation in neonatal rat cardiomyocytes.
Results
LRRK2 was upregulated in remodelled mouse hearts and cardiomyocytes. Cardiac hypertrophy, fibrosis and dysfunction were ameliorated in LRRK2 knockout mice. LRRK2 silencing protected against the PE-induced cardiomyocyte hypertrophic response, while LRRK2 over-expression worsened the PE-induced hypertrophic response in cardiomyocytes. Decreased autophagy was observed in remodelled cardiomyocytes, whereas LRRK2 silencing increased autophagy levels and LRRK2 overexpression reduced autophagy levels. The autophagy inhibitors 3-MA, bafilomycin and chloroquine reversed the protective effects of LRRK2 deficiency. The autophagy activator rapamycin reversed the deleterious effects of LRRK2 overexpression. We found that LRRK2 inhibited Bcl-2 phosphorylation, thus decreasing the phosphorylation of Beclin1. The protective effects of LRRK2 knockout were partly counteracted by Beclin1(+/-) in vivo and Beclin1 silencing in vitro. We also observed an interaction between LRRK2 and Rab7, an autolysosome degradation-associated protein, which caused Rab7 downregulation. Rab7 knockdown almost completely reversed LRRK2 silencing-induced protection of cardiomyocytes. Conclusion
LRRK2 deficiency protected against cardiac remodelling under pressure overload by increasing Bcl-2/Beclin1 and Rab7-regulated autophagy levels in the heart.
... Dead and dying cardiomyocytes showing characteristics of autophagy have been reported in HF patients. Analysis of hearts from patients with end-stage HF show CMs with cytoplasm replaced almost entirely with autophagosomes (Takemura et al., 2006), suggesting autophagic cell death to be the most prominent mechanism contributing to cell death in HF (Knaapen et al., 2001;Kostin et al., 2003). It is still undetermined whether an abnormal increase in autophagy causes CM death in animal models of HF. ...
... Treatment with granulocyte colonystimulating factor (G-CSF) significantly improved survival, cardiac function, and prevented remodeling in an animal model of HF. The cardioprotective effect was accompanied by the production and degradation of autophagosomes (Takemura et al., 2006) (Table 1). The central role of autophagy in HF development has been demonstrated across multiple studies where inhibition of autophagy such as miR-22 prevented post-AMI adverse remodeling along with improved cardiac function (Gupta et al., 2016). ...
Acute myocardial infarction (AMI) and heart failure (HF) that often follows is the leading causes of death and disability worldwide, exerting huge burdens on healthcare and economic resources. Therefore, new therapeutic approaches are required to reduce myocardial injury, improve cardiac repair, and prevent adverse myocardial remodelling, and the consequent HF. The death of cardiomyocytes (CMs) has been detected in the heart at all stages of AMI. In this context, autophagy, a catabolic process for the engulfment, degradation, and recycling of dysfunctional or damaged cellular components, plays a crucial role in CMs homeostasis, making it a key process in AMI and the development of HF. Autophagy induced by ischemia confers cardioprotection via the activation of adenosine monophosphate-activated protein kinase and inhibition of mTOR pathway, whereas further amplification of autophagy during reperfusion is maladaptive and exacerbates myocardial injury. As such, strategies that can modulate and normalize the autophagic response could prevent irreversible loss of cardiomyocytes in AMI and HF, thereby conferring cardioprotection. Here, we summarize the role of autophagy in AMI and HF as a potential target for cardioprotection, highlighting studies that focus on the development of new therapies that take advantage of autophagy modulation to prevent or delay the pathogenesis of AMI and progression to HF.
