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Anthracycline-Dependent Cardiotoxicity and Extracellular Matrix RemodelingAnthracycline-Dependent Cardiotoxicity FREE TO VIEW

Dragana Nikitovic, PhD; Ivo Juranek, MD, PhD; Martin F. Wilks, MD, PhD; Maria Tzardi, MD, PhD; Aristidis Tsatsakis, PhD; George N. Tzanakakis, MD, PhD
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From the Department of Anatomy-Histology-Embryology (Drs Nikitovic and Tzanakakis), the Department of Pathology (Dr Tzardi), and the Department of Forensic Sciences and Toxicology (Dr Tsatakis), School of Medicine, University of Crete, Heraklion, Greece; the Institute of Experimental Pharmacology and Toxicology (Dr Juranek), Slovak Academy of Sciences, Bratislava, Slovakia; and the Swiss Centre for Applied Human Toxicology (Dr Wilks), University of Basel, Basel, Switzerland.

CORRESPONDENCE TO: Dragana Nikitovic, PhD, Department of Anatomy-Histology-Embryology, School of Medicine, University of Crete, Voutes, Heraklion 71003, Greece; e-mail: dnikitovic@med.uoc.gr


Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details.


Chest. 2014;146(4):1123-1130. doi:10.1378/chest.14-0460
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The mechanisms of anthracycline-dependent cardiotoxicity have been studied widely, with the suggested principal mechanism of anthracycline damage being the generation of reactive oxygen species by iron-anthracycline complexes, leading to lipid peroxidation and membrane damage. An increasing number of researchers studying cardiovascular events associated with anthracycline-based chemotherapy are addressing cardiac extracellular matrix (ECM) remodeling. The heart is an efficient muscular pump, with the cardiomyocytes and intramural coronary vasculature of the heart tethered in an ECM consisting of a network of fibrillar, structural proteins, mostly collagens. Increasing evidence suggests that the ECM plays a complex and diverse role in the processes initiated by anthracycline-class drugs that lead to cardiac damage. This review discusses adverse myocardial remodeling induced by anthracyclines and focuses on their mechanisms of action.

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The term “cardiotoxicity” is generally used to define both a direct adverse effect of a toxic insult such as chemotherapy on the entire cardiovascular system and an indirect effect caused by a thrombogenic action or a hemodynamic flow alteration.1 An increasing number of studies of cardiovascular events associated with chemotherapy address cardiac extracellular matrix (ECM) remodeling. Historically, the myocardial ECM was thought to serve solely as a means of aligning cells and providing structure to the tissue. More recent evidence suggests that the ECM plays a complex and diverse role in processes initiated by anthracyclines, ultimately leading to cardiac damage. This review characterizes up-to-date findings on anthracycline-dependent adverse myocardial remodeling.

Anthracyclines are anticancer compounds derived originally from Streptomyces, and their antitumor activities were established in the 1960s.2 These red aromatic polyketides occur in a variety of forms because of the structural differences in the aglycone domain and the different sugar residues attached. The most important anthracycline family members are doxorubicin (DOX), daunorubicin and its derivative zorubicin, epirubicin, and related drugs, including mitoxantrone, bisantrene, aclacinomycin A, and amsacrine, which are all associated with cumulative dose-dependent cardiac toxicity.3,4

The exact triggers/mechanism by which anthracyclines inhibit cancer have so far not been established fully, and multiple pathways are thought to be involved in the cytotoxicity of this class of anticancer drugs. Anthracyclines enter the cells through passive diffusion,5 and, upon entry, the compounds can bind the proteasomes in the cytoplasm with high affinity. The drug-proteasome complex is then translocated into the nucleus.6 Importantly, the proteasomes have been shown to be located predominantly in the nucleus of neoplastic and normal proliferative cells, as compared with nonproliferative normal cells, which show the presence of proteasomes predominantly in the cytoplasm.7,8 Thus, the transport of anthracyclines into the nuclei of the neoplastic and nondifferentiated proliferative normal cells is facilitated. In the nucleus, the anthracyclines dissociate from the proteasome and bind the DNA because of their higher affinity for it, thus executing their DNA adenine methyltransferase-mediated effects. Indeed, intercalation into DNA, leading to inhibition of protein synthesis, was the first mechanism described for the cytotoxicity of anthracyclines.9

Parallel actions of anthracyclines have been suggested. For example, DOX at low concentrations has been shown to selectively displace nuclear proteins,10 whereas daunorubicin has been shown to induce the aggregation of chromatin.11 The proposed mechanism involves initial intercalation of the drug into the linker regions, where the DNA is free of nuclear proteins, leading to conformational changes in the DNA that extend toward the histone octamer and result in the unfolding of chromatin and its subsequent aggregation.12

Regulation of gene expression by inhibiting or promoting the binding of transcription factors is also considered to play a role in anthracycline cytotoxicity, with the potential involvement of SP-1 transcription factor as a specific target for these drugs.13 In addition, the inhibition of RNA polymerase and topoisomerase II activities has also been proposed.14 Modulation of p53 activities,15 induction of cytochrome c release from mitochondria,16 and mitogen-activated protein kinase (MAPK) activation17 are suggested proapoptopic effects mediated by anthracyclines. Moreover, one electron addition to the quinone moiety in ring C of anthracyclines initiates the formation of reactive oxygen species (ROS) such as superoxide anion radical and hydrogen peroxide.18 The one electron redox cycle of DOX has been demonstrated to induce the release of iron from its stores. DOX forms iron complexes that are capable of producing hydroxyl radical, the most potent ROS, as reviewed by Minotti et al.3 Because of their efficacy and broad-spectrum effect, anthracycline antibiotics continue to be widely used chemotherapeutic agents for treating a variety of cancers, despite their potential to elicit serious dose-dependent cardiotoxicity, often leading to degenerative cardiomyopathy/heart failure.19 Unfortunately, the therapeutic options against DOX-induced cardiomyopathy are very limited, and mostly involve supportive treatment, or cardiac transplant in severe cases.

According to American College of Cardiology and American Heart Association guidelines, patients receiving chemotherapy may be considered a Stage A heart failure group (defined as those with increased risk of developing cardiac dysfunction). Over the last years, recognition of the significance of the cardiac toxicity of anticancer treatment has increased markedly because of improvements in patient survival, aging of the general population (including patients with cancer), and the introduction of new anticancer drugs with unique toxicities.20 Anthracyclines can cause acute, subacute, and late cardiac damage.21,22 Acute morbidity occurs during or shortly after drug infusion and includes arrhythmias (supraventricular tachycardia, ventricular ectopy) accompanied, in some patients, by heart failure and pericarditis-myocarditis syndrome. The subacute cardiac toxicity occurs within a few weeks, clinically resembles myocarditis with edema and thickening of the left ventricular walls, and is accompanied by diastolic dysfunction and associated with increased mortality.22 Clinically, the most significant effect of anthracyclines is chronic cardiac toxicity leading to left ventricular dysfunction and congestive heart failure.22

The mechanisms of anthracycline-dependent cardiotoxicity have been studied widely, with the suggested principal mechanism being the generation of ROS by iron-anthracycline complexes, leading to lipid peroxidation and membrane damage21,23,24 and induction of apoptosis.17 ROS-mediated signaling has been recognized as a key modulator of both physiologic processes25 and different pathologic conditions, including cancer26 and inflammation.27 The extreme sensitivity of cardiac muscle to the ROS-induced damage caused by anthracyclines may be attributed to the relative deficiency of catalase28 and to the DOX-induced depletion of glutathione peroxidase.29 Parallel factors responsible for high cardiac susceptibility to anthracycline damage are the robust metabolic activity of the myocardium and its high concentration of cardiolipin, with its strong affinity for anthracyclines.30 When the rate of generation of the ROS overwhelms their rate of detoxification by endogenous antioxidant defenses, the mitochondrial inner-membrane permeability transition pore opens, enabling passive solute entry and consequent osmotic swelling of the mitochondria. Ultimately, these essential organelles degenerate, and the cardiomyocytes undergo necrosis. Thus, although the molecular basis of the cardiac damage remains to be elucidated, mitochondria are accepted as the main site of progressive molecular disorder31 and stress-induced activation of MAPK, therefore, modulating the response to anthracyclines and linking to apoptotic pathways.17

In mitochondria, DOX-induced ROS leads to the release of cytochrome c into the cytoplasm, resulting in an inhibition of the respiratory chain at the level of complex I.32 Mitochondria-derived ROS and calcium play a key role in stimulating DOX-induced “intrinsic and extrinsic forms” of apoptosis in cardiac cells, with Fas L expression via the nuclear factor of the activated T-lymphocytes signaling mechanism. Higher membrane permeability resulting from DOX-induced damage leads to an increased intracellular influx of calcium ions, impacting cardiac contraction and relaxation.33 Moreover, the changes in phospholipid homeostasis appear early after anthracycline insult.34 Anthracyclines can also disturb antioxidant defense systems and repair pathways controlling myocardial homeostasis.35 Immunologic aspects of DOX therapy have also been implicated.36 Another element in the pathomechanism of anthracycline-related cardiac damage is the involvement of paracrine growth and survival factors, as illustrated by the interaction with lapatinib (inhibitor of human epidermal growth factor receptor 2) in anthracycline-induced cardiac dysfunction.37 Importantly, the mechanisms responsible for anthracycline cardiotoxicity appear to be largely distinct from the mechanisms corresponding to its therapeutic action.

The heart is an efficient muscular pump, with the cardiomyocytes and intramural coronary vasculature of the heart tethered in an ECM consisting of a network of fibrillar, structural proteins, mostly collagens with the tensile strength of steel, as well as of proteoglycans, glycoproteins, and glycosaminoglycans. The stability of cardiac ECM and its dynamic equilibrium with cardiomyocytes are normally governed by interstitial fibroblasts and their turnover of collagen.38,39 Balanced turnover of collagen by cardiac fibroblasts can be lost under pathologic conditions. When collagen synthesis predominates over its degradation, the resulting interstitial and perivascular accumulation of collagen will lead to fibrosis. On the contrary, when degradation of collagen predominates over its synthesis, the resulting loss of collagen will lead to the disruption of the physiologic collagen scaffold. Alterations in the heart’s ECM can contribute significantly to a structural remodeling of the myocardium that leads to ventricular dysfunction during either diastolic or systolic phases of the cardiac cycle.40

Therefore, the primary mechanical role of the matrix is to provide a scaffold for myofiber alignment, which is protective against sarcomere overstretching. The collagenous matrix promotes transmission and coordination of the forces generated within myofibers to enable the physiologic contraction and expansion of the ventricular chambers during diastole. Moreover, the mechanical function of the matrix prevents myofiber slippage, sustains ventricular chamber geometry without wall thinning or deformation, and protects against myocardial rupture.41 In addition, the matrix has equally crucial, though secondary, roles integral to the functional and electrical behavior of the myocardium and vasomotor reactivity of its intramural coronary microvasculature. Thus, the continuum of the matrix network harmoniously facilitates apical-to-basal shortening of the heart. Together with its sequential depolarization, myocardial shortening resembles a peristaltic pump that empties itself in an apical-to-basal direction.42 Therefore, the impact of the matrix on the normal functioning of the heart is highly significant.40

In anthracycline cardiotoxicity, acute and chronic responses can be distinguished. Importantly, both types of toxicity have distinct effects on ECM remodeling. In an acute DOX model, microarray and network analyses showed that DOX damage was associated with changes in a large cohort of gene expressions, many of which were inversely regulated by thrombopoietin, including modulators of signal transduction, ion transport, antiapoptosis, protein kinase B (Akt)/p42/p44 extracellular signal-regulated kinase pathways, cell division, and contractile protein/matrix remodeling.43 The matrix metalloproteinases (MMPs) (MMP-2 and MMP-9) gene expressions were stimulated in the ventricle after treatment with DOX, suggesting that these ECM remodeling effectors may play an important role in the development of DOX-induced cardiotoxicity.44 An in vitro study of cardiomyocytes demonstrated that DOX induced a significant increase in ROS formation and a rapid increase of MMP expression and activation. Furthermore, p38 was identified as the MAPK mainly responsible for MMP-9 activation through a nicotinamide adenine dinucleotide phosphate (NAD[P]H)-independent mechanism, whereas the c-Jun N-terminal kinase/NAD(P)H oxidase cascade is an important pathway that mediates DOX signaling to MMP-2.45 Therefore, MMP activation is postulated to be an important early event in DOX-induced cardiotoxicity.

In addition to ROS, nitric oxide, previously determined to be an important redox regulator46 of the cardiovascular system,47 was shown to be increased in DOX-treated in vitro and in vivo models.48 These authors postulated that the concomitant production of peroxynitrite was responsible for MMP-2/MMP-9 gene expression and poly(ADP-ribose) polymerase activation, as well as for decreases in myocardial contractility, catalase, and glutathione peroxidase activities 5 days after DOX treatment in mice. Along the same lines, a strong activation of MMP-1, MMP-2, MMP-9, and MT1-MMP, with typical signs of myocardial fibrosis, myocardial cell loss, collagen disorder, and vacuoles, was evident in acute DOX-induced cardiac remodeling.49 In another study, the damage to the myocardium after a single injection of a therapeutic dose of DOX was followed by a distinctly reduced density of fibronectin distribution and a decreased content of tubulin, fibronectin, kinase-related protein (or telokin), and smooth muscle/nonmuscle myosin light-chain kinase. On the other hand, DOX treatment did not influence the relative volume and structure of the collagen network.50 DOX also induces actin cytoskeleton reorganization associated with cell shrinkage, detachment, and predetachment apoptosis. The Rho kinase isoform 2 was found to be required, to stabilize the actin cytoskeleton and cell adhesion through regulating cofilin phosphorylation in response to cytotoxic stress induced by DOX.51 Indeed, the dysregulation of protein folding, translational regulation, and cytoskeleton regulation by DOX-induced oxidative stress in cardiomyocytes52 suggests that this drug strongly affects the cell-ECM interface. Moreover, acute DOX effects involve endothelium participation. The loss of extracellular superoxide dismutase and DOX-induced oxidative injury led to increases in shed syndecan-1 in the serum, originating from the endothelium of the vasculature, which facilitated the proliferation of primary mouse cardiac fibroblasts, ultimately supporting heart fibrosis.53

After the initial cardiomyocyte-dependent toxic effects, inflammatory cells are guided by a gradient in the concentrations of tissue chemokines to the site of both ischemic or, as in case of DOX-toxicity, nonischemic injury, where they then participate in a wound-healing response. Their function is to degrade and remove dead cells by proteolysis and phagocytosis, respectively, and this function is supported by the digestion of fibrillar collagen by MMPs already activated by ROS and cytokines.54 With the upregulation of the tissue-based inhibitors of MMPs (TIMPs), the degradative phase of repair is mostly accomplished by day 7 after the onset of necrosis.54

Myofibroblasts, chemotactically stimulated by inflammatory cells,55 generate, in turn, the fibrogenic cytokine transforming growth factor-β1, which regulates the deposition of matrix proteins (including fibronectin, fibrillar collagen types I and III, and proteoglycans) and inhibitors of matrix degradation, which are integral to tissue repair and scarring following cardiomyocyte necrosis.56 In a rabbit heart-failure model induced by daunorubicin, dramatic changes in basement membrane proteins and ECM were documented when two-dimensional polyacrylamide gel electrophoresis proteomic analysis was applied.57 There is evidence that myocardial ECM deposition is preceded by infiltration into the myocardium by cells that express a combination of hematopoietic (ED1, CD133) and mesenchymal (SMA) cell markers, which is a characteristic of the phenotype of fibroblast precursor cells termed fibrocytes. This suggests that fibrocytes, rather than leukocytes, may have effector functions in the initiation of myocardial fibrosis.58 In addition, as discussed comprehensively by Weber et al,40 the ECM plays a crucial role not only as a site for sequestration and storage, but also in the controlled release and modulated availability of cytokines. These ongoing processes result in the new but considerably weaker collagen matrix formation (scar) at the site of injury, which is established 6 to 8 weeks after the onset of cardiomyocyte injury.59 Therefore, the chronic effects of anthracycline treatment are correlated to extensive cardiac tissue ECM remodeling.

Specifically, chronic DOX effects caused marked heterogeneous subcellular alterations of cardiomyocytes and structural disorganizations of the cardiac ECM. The effects of DOX were linked to a stimulation of plasma MMP-2 and MMP-9 activities that had already increased by 4 weeks after the end of the treatment. In the left ventricle, however, DOX led only to increased MMP-2 activation at 8 weeks after the end of treatment. These changes in tissue MMP-2 were connected to the stimulation of Akt activation, the inhibition of superoxide dismutase, an increase in superoxide levels, and induction of inducible nitric oxide synthase protein expression and caspase-3.60

Similarly, the chronic DOX cardiomyopathy model was characterized by increased MMP and decreased TIMP-3 expression.61 Likewise, morphologic changes in the myocardium of daunorubicin-treated animals were characterized by focal myocardial interstitial fibrosis of different intensities, marked by an increased content of both collagen types I and III. Moreover, an increased MMP-2 expression in both cardiomyocytes and fibroblasts was determined.62 Other ECM components were found to have a protective function against chronic DOX-induced effects, as demonstrated in a study by van Almen et al.63 The absence of matricellular protein thrombospondin-2 (TSP-2), known for its matrix-preserving function and for modulating cellular function, was found to increase cardiomyocyte damage and matrix disruption in DOX-induced cardiomyopathy. Enhanced myocyte damage in the absence of TSP-2 was associated with impaired activation of the Akt signaling pathway, enhanced matrix disruption, and increased matrix MMP-2 levels. Importantly, the inhibition of Akt phosphorylation in cardiomyocytes significantly reduced TSP-2 expression, unveiling a unique feedback loop between Akt and TSP-2.63 When cardiomyopathy was induced in mice by the chronic administration of DOX, elevated cystatin C protein was detected in the plasma analogously to the myocardial ischemia caused by left anterior descending coronary artery occlusion. In myocardial tissue from the ischemic area, an increase in cystatin C correlated with the inhibition of cathepsin B activity and the accumulation of fibronectin and collagen I/III.64 These findings suggest that the emphasis must be placed on the fine balance and regulation of both cathepsins and cystatins, with an imbalance resulting in a pathologic state caused by deficient or excessive degradation of collagen and other structural components of the myocardial ECM.64

Importantly, ROS-mediated effects contribute significantly to chronic cardiac toxicity induced by anthracyclines. Thus, in response to DOX, Nox2−/− mice, compared with wild-type control animals, exhibited less myocardial atrophy, cardiomyocyte apoptosis, and interstitial fibrosis, together with reduced increases in profibrotic gene expression (procollagen IIIαI, transforming growth factor-β3, and connective tissue growth factor) and MMP-9 activity. These alterations were associated with beneficial changes in NAD(P)H oxidase activity, oxidative/nitrosative stress, and inflammatory cell infiltration. Therefore, Zhao et al65 suggest that Nox2 promotes pathologic cardiac remodeling associated with DOX chemotherapy. In contrast, Jirkovsky et al66 suggest that global oxidative stress need not be a factor in the development of anthracycline-induced heart failure, whereas the suppression of mitochondrial biogenesis may be involved. The putative anthracycline-induced mechanisms of adverse cardiac matrix remodeling are presented schematically in Fig 1.

Figure Jump LinkFigure 1 –  Schematic presentation of anthracycline (ANT)-induced cardiac matrix remodeling: transcriptional regulation of enzymes involved in collagen and fibronectin turnover (A); changes induced by ANT at cell-ECM interface involving IL-kinase action and actin cytoskeleton remodeling (B); collagen degradation and turnover induced by MMP activities (C); modulation of cystatin C/cathepsin equilibrium regulating fibronectin turnover (D); and SDC-1 extracellular domain shedding correlated to myofibroblast proliferation (E). ECM = extracellular matrix; ERK = extracellular signal-regulated kinase; IL-kinase = integrin-linked kinase; JNK = C-jun N-terminal kinase; MMP = matrix metalloproteinase; MT1 = membrane type 1 matrix metalloproteinase; NAD(P)H = nicotinamide adenine dinucleotide phosphate; RNS = reactive nitrogen species; ROS = reactive oxygen species; SDC = syndecan-1.Grahic Jump Location

The risk of cardiac complications is relatively lower with the use of a DOX analog (epirubicin67 or liposome-encapsulated DOX), characterized by reduced myocardial concentration and lower peak serum concentration of its active metabolite.68 Indeed, enhanced antitumor efficacy and reduced systemic toxicity of sulfatide-containing liposomal DOX in a xenograft model of colorectal cancer has been described.68 Sulfatide is a glycosphingolipid known to interact with several ECM proteins, such as tenascin-C, which is overexpressed in many types of cancer, including that of the colon. The use of this nanodrug delivery system to deliver DOX for the treatment of tumor-bearing mice produced a much improved therapeutic efficacy in terms of tumor growth suppression and extended survival in contrast to the free drug. Furthermore, treatment of tumor-bearing mice with sulfatide-containing liposomal DOX resulted in a lower DOX uptake in the principal sites of toxicity of the free drug, namely, the heart and skin, as well as reduced myelosuppression and diminished cardiotoxicity. Such natural lipid-guided nanodrug delivery systems may represent a new strategy for the development of effective anticancer chemotherapeutics targeting the tumor microenvironment for both the primary tumor and micrometastases.

Another proposed approach for dealing with DOX-mediated oxidant-induced toxicity in cardiac cells is the exploitation of the hyperthermia-induced small heat shock protein, which acts as an endogenous antioxidant against DOX-derived oxidants such as hydrogen peroxide. Heat shock-induced small heat shock protein was found to act as an antiapoptotic protein (reducing ROS and Bax-to-Bcl2 ratio) against DOX, and its phosphorylated isoforms stabilized F-actin remodeling in DOX-treated cardiac cells and, hence, attenuated the toxicity.69 Blocking of angiotensin II (Ang II) excessive signaling seems like a promising venue, as illustrated in a Daunorubicin toxicity rat model, in which the use of an Ang II receptor blocker downregulated MMP-2 expression and myocardial expression of Ang II, attenuated the increased protein expressions of p67phox and Nox4, and reduced oxidative stress-induced DNA damage.70 Another potential target could be integrin-linked kinase, a multifunctional kinase linking the ECM to intracellular signaling pathways, whose activation in the heart gives rise to a number of functional consequences. Indeed, integrin-linked kinase gene therapy improved cardiac function and survival in a model of DOX-induced dilated cardiomyopathy, and this may be mediated through the suppression of inflammation, the prevention of ventricular remodeling, the inhibition of cardiomyocyte apoptosis and autophagy, and the stimulation of cardiomyocyte proliferation.71 Taking into account the importance of ECM remodeling to anthracycline cardiotoxicity, it is suggested that the regulation of matrix protease pathways such as the MMPs and the TIMPs will likely yield a new avenue of diagnostic and therapeutic strategies for myocardial remodeling and the progression to heart failure.

The cardiac ECM provides a structural and mechanistic scaffold that supports physiologic cardiac function. Increasing evidence illustrates the extent and importance of ECM remodeling in response to anthracycline exposure. Understanding the cellular and molecular triggers that, in turn, give rise to changes in the cardiac ECM could provide opportunities to modify the remodeling process, thereby better exploiting the potent antitumor properties of this class of chemotherapeutic agents while reducing their toxic side effects.

Financial/nonfinancial disclosures: The authors have reported to CHEST that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.

Akt

protein kinase B

Ang II

angiotensin II

DOX

doxorubicin

ECM

extracellular matrix

MAPK

mitogen-activated protein kinase

MMP

matrix metalloproteinase

NAD(P)H

nicotinamide adenine dinucleotide phosphate

ROS

reactive oxygen species

TIMP

tissue-based inhibitor of matrix metalloproteinase

TSP-2

thrombospondin-2

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Weber KT, Sun Y, Bhattacharya SK, Ahokas RA, Gerling IC. Myofibroblast-mediated mechanisms of pathological remodelling of the heart. Nat Rev Cardiol. 2013;10(1):15-26. [CrossRef] [PubMed]
 
Robinson TF, Geraci MA, Sonnenblick EH, Factor SM. Coiled perimysial fibers of papillary muscle in rat heart: morphology, distribution, and changes in configuration. Circ Res. 1988;63(3):577-592. [CrossRef] [PubMed]
 
Rushmer RF, Thal N. The mechanics of ventricular contraction; a cinefluorographic study. Circulation. 1951;4(2):219-228. [CrossRef] [PubMed]
 
Chan KY, Xiang P, Zhou L, et al. Thrombopoietin protects against doxorubicin-induced cardiomyopathy, improves cardiac function, and reversely alters specific signalling networks. Eur J Heart Fail. 2011;13(4):366-376. [CrossRef] [PubMed]
 
Kizaki K, Ito R, Okada M, et al. Enhanced gene expression of myocardial matrix metalloproteinases 2 and 9 after acute treatment with doxorubicin in mice. Pharmacol Res. 2006;53(4):341-346. [CrossRef] [PubMed]
 
Spallarossa P, Altieri P, Garibaldi S, et al. Matrix metalloproteinase-2 and -9 are induced differently by doxorubicin in H9c2 cells: The role of MAP kinases and NAD(P)H oxidase. Cardiovasc Res. 2006;69(3):736-745. [CrossRef] [PubMed]
 
Nikitovic D, Holmgren A. S-nitrosoglutathione is cleaved by the thioredoxin system with liberation of glutathione and redox regulating nitric oxide. J Biol Chem. 1996;271(32):19180-19185. [CrossRef] [PubMed]
 
Nikitovic D, Zacharis EA, Manios EG, et al. Plasma levels of nitrites/nitrates in patients with chronic atrial fibrillation are increased after electrical restoration of sinus rhythm. J Interv Card Electrophysiol. 2002;7(2):171-176. [CrossRef] [PubMed]
 
Mukhopadhyay P, Rajesh M, Bátkai S, et al. Role of superoxide, nitric oxide, and peroxynitrite in doxorubicin-induced cell death in vivo and in vitro. Am J Physiol Heart Circ Physiol. 2009;296(5):H1466-H1483. [CrossRef] [PubMed]
 
Goetzenich A, Hatam N, Zernecke A, et al. Alteration of matrix metalloproteinases in selective left ventricular adriamycin-induced cardiomyopathy in the pig. J Heart Lung Transplant. 2009;28(10):1087-1093. [CrossRef] [PubMed]
 
Dudnakova TV, Lakomkin VL, Tsyplenkova VG, Shekhonin BV, Shirinsky VP, Kapelko VI. Alterations in myocardial cytoskeletal and regulatory protein expression following a single Doxorubicin injection. J Cardiovasc Pharmacol. 2003;41(5):788-794. [CrossRef] [PubMed]
 
Shi J, Wu X, Surma M, et al. Distinct roles for ROCK1 and ROCK2 in the regulation of cell detachment. Cell Death Dis. 2013;4:e483. [CrossRef] [PubMed]
 
Lin ST, Chou HC, Chen YW, Chan HL. Redox-proteomic analysis of doxorubicin-induced altered thiol activity in cardiomyocytes. Mol Biosyst. 2013;9(3):447-456. [CrossRef] [PubMed]
 
Kliment CR, Suliman HB, Tobolewski JM, et al. Extracellular superoxide dismutase regulates cardiac function and fibrosis. J Mol Cell Cardiol. 2009;47(5):730-742. [CrossRef] [PubMed]
 
Cleutjens JPM, Kandala JC, Guarda E, Guntaka RV, Weber KT. Regulation of collagen degradation in the rat myocardium after infarction. J Mol Cell Cardiol. 1995;27(6):1281-1292. [CrossRef] [PubMed]
 
Sun Y, Zhang JQ, Zhang J, Ramires FJA. Angiotensin II, transforming growth factor-β1 and repair in the infarcted heart. J Mol Cell Cardiol. 1998;30(8):1559-1569. [CrossRef] [PubMed]
 
Horiguchi M, Ota M, Rifkin DB. Matrix control of transforming growth factor-β function. J Biochem. 2012;152(4):321-329. [CrossRef] [PubMed]
 
Stěrba M, Popelová O, Lenčo J, et al. Proteomic insights into chronic anthracycline cardiotoxicity. J Mol Cell Cardiol. 2011;50(5):849-862. [CrossRef] [PubMed]
 
Sopel M, Falkenham A, Oxner A, Ma I, Lee TD, Légaré JF. Fibroblast progenitor cells are recruited into the myocardium prior to the development of myocardial fibrosis. Int J Exp Pathol. 2012;93(2):115-124. [CrossRef] [PubMed]
 
Fomovsky GM, Rouillard AD, Holmes JW. Regional mechanics determine collagen fiber structure in healing myocardial infarcts. J Mol Cell Cardiol. 2012;52(5):1083-1090. [CrossRef] [PubMed]
 
Ivanová M, Dovinová I, Okruhlicová L, et al. Chronic cardiotoxicity of doxorubicin involves activation of myocardial and circulating matrix metalloproteinases in rats. Acta Pharmacol Sin. 2012;33(4):459-469. [CrossRef] [PubMed]
 
Aupperle H, Garbade J, Schubert A, et al. Effects of autologous stem cells on immunohistochemical patterns and gene expression of metalloproteinases and their tissue inhibitors in doxorubicin cardiomyopathy in a rabbit model. Vet Pathol. 2007;44(4):494-503. [CrossRef] [PubMed]
 
Adamcová M, Potáčová A, Popelová O, et al. Cardiac remodeling and MMPs on the model of chronic daunorubicin-induced cardiomyopathy in rabbits. Physiol Res. 2010;59(5):831-836. [PubMed]
 
van Almen GC, Swinnen M, Carai P, et al. Absence of thrombospondin-2 increases cardiomyocyte damage and matrix disruption in doxorubicin-induced cardiomyopathy. J Mol Cell Cardiol. 2011;51(3):318-328. [CrossRef] [PubMed]
 
Xie L, Terrand J, Xu B, Tsaprailis G, Boyer J, Chen QM. Cystatin C increases in cardiac injury: a role in extracellular matrix protein modulation. Cardiovasc Res. 2010;87(4):628-635. [CrossRef] [PubMed]
 
Zhao Y, McLaughlin D, Robinson E, et al. Nox2 NADPH oxidase promotes pathologic cardiac remodeling associated with Doxorubicin chemotherapy. Cancer Res. 2010;70(22):9287-9297. [CrossRef] [PubMed]
 
Jirkovsky E, Popelová O, Kriváková-Stanková P, et al. Chronic anthracycline cardiotoxicity: molecular and functional analysis with focus on nuclear factor erythroid 2-related factor 2 and mitochondrial biogenesis pathways. J Pharmacol Exp Ther. 2012;343(2):468-478. [CrossRef] [PubMed]
 
Burnell M, Levine MN, Chapman JA, et al. Cyclophosphamide, epirubicin, and Fluorouracil versus dose-dense epirubicin and cyclophosphamide followed by Paclitaxel versus Doxorubicin and cyclophosphamide followed by Paclitaxel in node-positive or high-risk node-negative breast cancer. J Clin Oncol. 2010;28(1):77-82. [CrossRef] [PubMed]
 
Lin J, Yu Y, Shigdar S, et al. Enhanced antitumor efficacy and reduced systemic toxicity of sulfatide-containing nanoliposomal doxorubicin in a xenograft model of colorectal cancer. PLoS ONE. 2012;7(11):e49277. [CrossRef] [PubMed]
 
Venkatakrishnan CD, Tewari AK, Moldovan L, et al. Heat shock protects cardiac cells from doxorubicin-induced toxicity by activating p38 MAPK and phosphorylation of small heat shock protein 27. Am J Physiol Heart Circ Physiol. 2006;291(6):H2680-H2691. [CrossRef] [PubMed]
 
Arozal W, Watanabe K, Veeraveedu PT, et al. Effect of telmisartan in limiting the cardiotoxic effect of daunorubicin in rats. J Pharm Pharmacol. 2010;62(12):1776-1783. [CrossRef] [PubMed]
 
Gu R, Bai J, Ling L, et al. Increased expression of integrin-linked kinase improves cardiac function and decreases mortality in dilated cardiomyopathy model of rats. PLoS ONE. 2012;7(2):e31279. [CrossRef] [PubMed]
 

Figures

Figure Jump LinkFigure 1 –  Schematic presentation of anthracycline (ANT)-induced cardiac matrix remodeling: transcriptional regulation of enzymes involved in collagen and fibronectin turnover (A); changes induced by ANT at cell-ECM interface involving IL-kinase action and actin cytoskeleton remodeling (B); collagen degradation and turnover induced by MMP activities (C); modulation of cystatin C/cathepsin equilibrium regulating fibronectin turnover (D); and SDC-1 extracellular domain shedding correlated to myofibroblast proliferation (E). ECM = extracellular matrix; ERK = extracellular signal-regulated kinase; IL-kinase = integrin-linked kinase; JNK = C-jun N-terminal kinase; MMP = matrix metalloproteinase; MT1 = membrane type 1 matrix metalloproteinase; NAD(P)H = nicotinamide adenine dinucleotide phosphate; RNS = reactive nitrogen species; ROS = reactive oxygen species; SDC = syndecan-1.Grahic Jump Location

Tables

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Weber KT. Cardiac interstitium in health and disease: the fibrillar collagen network. J Am Coll Cardiol. 1989;13(7):1637-1652. [CrossRef] [PubMed]
 
Weber KT, Sun Y, Bhattacharya SK, Ahokas RA, Gerling IC. Myofibroblast-mediated mechanisms of pathological remodelling of the heart. Nat Rev Cardiol. 2013;10(1):15-26. [CrossRef] [PubMed]
 
Robinson TF, Geraci MA, Sonnenblick EH, Factor SM. Coiled perimysial fibers of papillary muscle in rat heart: morphology, distribution, and changes in configuration. Circ Res. 1988;63(3):577-592. [CrossRef] [PubMed]
 
Rushmer RF, Thal N. The mechanics of ventricular contraction; a cinefluorographic study. Circulation. 1951;4(2):219-228. [CrossRef] [PubMed]
 
Chan KY, Xiang P, Zhou L, et al. Thrombopoietin protects against doxorubicin-induced cardiomyopathy, improves cardiac function, and reversely alters specific signalling networks. Eur J Heart Fail. 2011;13(4):366-376. [CrossRef] [PubMed]
 
Kizaki K, Ito R, Okada M, et al. Enhanced gene expression of myocardial matrix metalloproteinases 2 and 9 after acute treatment with doxorubicin in mice. Pharmacol Res. 2006;53(4):341-346. [CrossRef] [PubMed]
 
Spallarossa P, Altieri P, Garibaldi S, et al. Matrix metalloproteinase-2 and -9 are induced differently by doxorubicin in H9c2 cells: The role of MAP kinases and NAD(P)H oxidase. Cardiovasc Res. 2006;69(3):736-745. [CrossRef] [PubMed]
 
Nikitovic D, Holmgren A. S-nitrosoglutathione is cleaved by the thioredoxin system with liberation of glutathione and redox regulating nitric oxide. J Biol Chem. 1996;271(32):19180-19185. [CrossRef] [PubMed]
 
Nikitovic D, Zacharis EA, Manios EG, et al. Plasma levels of nitrites/nitrates in patients with chronic atrial fibrillation are increased after electrical restoration of sinus rhythm. J Interv Card Electrophysiol. 2002;7(2):171-176. [CrossRef] [PubMed]
 
Mukhopadhyay P, Rajesh M, Bátkai S, et al. Role of superoxide, nitric oxide, and peroxynitrite in doxorubicin-induced cell death in vivo and in vitro. Am J Physiol Heart Circ Physiol. 2009;296(5):H1466-H1483. [CrossRef] [PubMed]
 
Goetzenich A, Hatam N, Zernecke A, et al. Alteration of matrix metalloproteinases in selective left ventricular adriamycin-induced cardiomyopathy in the pig. J Heart Lung Transplant. 2009;28(10):1087-1093. [CrossRef] [PubMed]
 
Dudnakova TV, Lakomkin VL, Tsyplenkova VG, Shekhonin BV, Shirinsky VP, Kapelko VI. Alterations in myocardial cytoskeletal and regulatory protein expression following a single Doxorubicin injection. J Cardiovasc Pharmacol. 2003;41(5):788-794. [CrossRef] [PubMed]
 
Shi J, Wu X, Surma M, et al. Distinct roles for ROCK1 and ROCK2 in the regulation of cell detachment. Cell Death Dis. 2013;4:e483. [CrossRef] [PubMed]
 
Lin ST, Chou HC, Chen YW, Chan HL. Redox-proteomic analysis of doxorubicin-induced altered thiol activity in cardiomyocytes. Mol Biosyst. 2013;9(3):447-456. [CrossRef] [PubMed]
 
Kliment CR, Suliman HB, Tobolewski JM, et al. Extracellular superoxide dismutase regulates cardiac function and fibrosis. J Mol Cell Cardiol. 2009;47(5):730-742. [CrossRef] [PubMed]
 
Cleutjens JPM, Kandala JC, Guarda E, Guntaka RV, Weber KT. Regulation of collagen degradation in the rat myocardium after infarction. J Mol Cell Cardiol. 1995;27(6):1281-1292. [CrossRef] [PubMed]
 
Sun Y, Zhang JQ, Zhang J, Ramires FJA. Angiotensin II, transforming growth factor-β1 and repair in the infarcted heart. J Mol Cell Cardiol. 1998;30(8):1559-1569. [CrossRef] [PubMed]
 
Horiguchi M, Ota M, Rifkin DB. Matrix control of transforming growth factor-β function. J Biochem. 2012;152(4):321-329. [CrossRef] [PubMed]
 
Stěrba M, Popelová O, Lenčo J, et al. Proteomic insights into chronic anthracycline cardiotoxicity. J Mol Cell Cardiol. 2011;50(5):849-862. [CrossRef] [PubMed]
 
Sopel M, Falkenham A, Oxner A, Ma I, Lee TD, Légaré JF. Fibroblast progenitor cells are recruited into the myocardium prior to the development of myocardial fibrosis. Int J Exp Pathol. 2012;93(2):115-124. [CrossRef] [PubMed]
 
Fomovsky GM, Rouillard AD, Holmes JW. Regional mechanics determine collagen fiber structure in healing myocardial infarcts. J Mol Cell Cardiol. 2012;52(5):1083-1090. [CrossRef] [PubMed]
 
Ivanová M, Dovinová I, Okruhlicová L, et al. Chronic cardiotoxicity of doxorubicin involves activation of myocardial and circulating matrix metalloproteinases in rats. Acta Pharmacol Sin. 2012;33(4):459-469. [CrossRef] [PubMed]
 
Aupperle H, Garbade J, Schubert A, et al. Effects of autologous stem cells on immunohistochemical patterns and gene expression of metalloproteinases and their tissue inhibitors in doxorubicin cardiomyopathy in a rabbit model. Vet Pathol. 2007;44(4):494-503. [CrossRef] [PubMed]
 
Adamcová M, Potáčová A, Popelová O, et al. Cardiac remodeling and MMPs on the model of chronic daunorubicin-induced cardiomyopathy in rabbits. Physiol Res. 2010;59(5):831-836. [PubMed]
 
van Almen GC, Swinnen M, Carai P, et al. Absence of thrombospondin-2 increases cardiomyocyte damage and matrix disruption in doxorubicin-induced cardiomyopathy. J Mol Cell Cardiol. 2011;51(3):318-328. [CrossRef] [PubMed]
 
Xie L, Terrand J, Xu B, Tsaprailis G, Boyer J, Chen QM. Cystatin C increases in cardiac injury: a role in extracellular matrix protein modulation. Cardiovasc Res. 2010;87(4):628-635. [CrossRef] [PubMed]
 
Zhao Y, McLaughlin D, Robinson E, et al. Nox2 NADPH oxidase promotes pathologic cardiac remodeling associated with Doxorubicin chemotherapy. Cancer Res. 2010;70(22):9287-9297. [CrossRef] [PubMed]
 
Jirkovsky E, Popelová O, Kriváková-Stanková P, et al. Chronic anthracycline cardiotoxicity: molecular and functional analysis with focus on nuclear factor erythroid 2-related factor 2 and mitochondrial biogenesis pathways. J Pharmacol Exp Ther. 2012;343(2):468-478. [CrossRef] [PubMed]
 
Burnell M, Levine MN, Chapman JA, et al. Cyclophosphamide, epirubicin, and Fluorouracil versus dose-dense epirubicin and cyclophosphamide followed by Paclitaxel versus Doxorubicin and cyclophosphamide followed by Paclitaxel in node-positive or high-risk node-negative breast cancer. J Clin Oncol. 2010;28(1):77-82. [CrossRef] [PubMed]
 
Lin J, Yu Y, Shigdar S, et al. Enhanced antitumor efficacy and reduced systemic toxicity of sulfatide-containing nanoliposomal doxorubicin in a xenograft model of colorectal cancer. PLoS ONE. 2012;7(11):e49277. [CrossRef] [PubMed]
 
Venkatakrishnan CD, Tewari AK, Moldovan L, et al. Heat shock protects cardiac cells from doxorubicin-induced toxicity by activating p38 MAPK and phosphorylation of small heat shock protein 27. Am J Physiol Heart Circ Physiol. 2006;291(6):H2680-H2691. [CrossRef] [PubMed]
 
Arozal W, Watanabe K, Veeraveedu PT, et al. Effect of telmisartan in limiting the cardiotoxic effect of daunorubicin in rats. J Pharm Pharmacol. 2010;62(12):1776-1783. [CrossRef] [PubMed]
 
Gu R, Bai J, Ling L, et al. Increased expression of integrin-linked kinase improves cardiac function and decreases mortality in dilated cardiomyopathy model of rats. PLoS ONE. 2012;7(2):e31279. [CrossRef] [PubMed]
 
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