Smad3 promotes adverse cardiovascular remodeling and dysfunction in doxorubicin-treated hearts.

Many anticancer therapies cause serious cardiovascular complications that degrade quality of life and cause early mortality in treated patients. Specifically, doxorubicin is known as an effective anticancer agent that causes cardiomyopathy in treated patients. There has been growing interest in defining the role of endothelial cells in cardiac damage by doxorubicin.

The TGF-β pathway mediates doxorubicin effects on cardiac endothelial cells.

Elevated ALK4/5 ligands including TGF-β and activins have been linked to cardiovascular remodeling and heart failure. Doxorubicin (Dox) is commonly used as a model of cardiomyopathy, a condition that often precedes cardiovascular remodeling and heart failure. In 7-8-week-old C57Bl/6 male mice treated with Dox we found decreased capillary density, increased levels of ALK4/5 ligand and Smad2/3 transcripts, and increased expression of Smad2/3 transcriptional targets.

Stretch-induced hypertrophy activates NFkB-mediated VEGF secretion in adult cardiomyocytes.

Hypertension and myocardial infarction are associated with the onset of hypertrophy. Hypertrophy is a compensatory response mechanism to increases in mechanical load due to pressure or volume overload. It is characterized by extracellular matrix remodeling and hypertrophic growth of adult cardiomyocytes.

Analysis of proteome changes in doxorubicin-treated adult rat cardiomyocyte.

Doxorubicin-induced cardiomyopathy in cancer patients is well established. The proposed mechanism of cardiac damage includes generation of reactive oxygen species, mitochondrial dysfunction and cardiomyocyte apoptosis. Exposure of adult rat cardiomyocytes to low levels of DOX for 48h induced apoptosis.

Doxorubicin inactivates myocardial cytochrome c oxidase in rats: cardioprotection by Mito-Q.

Doxorubicin (DOX) is used for treating various cancers. Its clinical use is, however, limited by its dose-limiting cardiomyopathy. The exact mechanism of DOX-induced cardiomyopathy still remains unknown.

Differences in doxorubicin-induced apoptotic signaling in adult and immature cardiomyocytes.

A proposed mechanism for the cardiotoxicity of doxorubicin (DOX) involves apoptosis in cardiomyocytes. In the study described here, we investigated the molecular basis for the differences in DOX-induced toxicity in adult rat cardiomyocytes (ARCM), neonatal rat cardiomyocytes (NRCM), and rat embryonic H9c2 cardiomyoblasts. Activation of caspase-9 and -3 was considerably lower in DOX-treated ARCM as compared with NRCM and H9c2 cardiomyoblasts.

Cytokines and lipopolysaccharides induce inducible nitric oxide synthase but not enzyme activity in adult rat cardiomyocytes.

There is evidence that nitric oxide (NO) formation in adult cardiomyocytes stimulated with lipopolysaccharide (LPS) is not commensurate with iNOS levels. Tetrahydrobiopterin (BH(4)) is a key factor in the stabilization and NO production by iNOS homodimer. Thus we hypothesized that BH(4) is a limiting factor for NO production in adult cardiomyocytes in response to LPS and cytokines (TNF-alpha, IL-1, IFN-gamma alone, or mixed).

Mitochondrial big conductance KCa channel and cardioprotection in infant rabbit heart.

Chronic hypoxia increases resistance to myocardial ischemia in infants. Activation of the mitochondrial big conductance Ca(2+) -sensitive K channel (mitoBKCa) has been shown to be protective in adult hearts; however, its role in infant hearts is unknown. Hearts from normoxic or hypoxic infant rabbits were perfused with a mitoKCa opener, NS1619, or blocker Paxilline before ischemia and reperfusion.

Early detection of doxorubicin cardiomyopathy using two-dimensional strain echocardiography.

Doxorubicin is one of the most effective chemotherapeutic agents; however, it causes dose-dependent cardiomyopathy that may lead to heart failure. Conventional measures of ventricular function, such as fractional shortening, are insensitive in detecting early doxorubicin cardiomyopathy. We tested whether novel two-dimensional radial strain echocardiography (2DSE) can detect early doxorubicin injury following chronic administration in a rat model.

Doxorubicin activates nuclear factor of activated T-lymphocytes and Fas ligand transcription: role of mitochondrial reactive oxygen species and calcium.

Doxorubicin (DOX), a widely used antitumour drug, causes dose-dependent cardiotoxicity. Cardiac mitochondria represent a critical target organelle of toxicity during DOX chemotherapy. Proposed mechanisms include generation of ROS (reactive oxygen species) and disturbances in mitochondrial calcium homoeostasis.

Changes in tetrahydrobiopterin levels in endothelial cells and adult cardiomyocytes induced by LPS and hydrogen peroxide--a role for GFRP?

Alterations in tetrahydrobiopterin (BH4) levels have significant consequences in vascular pathophysiology. However, the mechanisms regulating BH4 remain poorly understood. The activity of GTP cyclohydrolase I (GTPCH-I), the first enzyme in BH4 biosynthesis, is controlled by protein levels, posttranslational modifications and interaction with GTPCH-I feedback regulatory protein (GFRP).

Doxorubicin induces apoptosis in normal and tumor cells via distinctly different mechanisms. intermediacy of H(2)O(2)- and p53-dependent pathways.

Doxorubicin (DOX), a widely used chemotherapeutic agent, exhibits cardiotoxicity as an adverse side effect in cancer patients. DOX-mediated cardiomyopathy is linked to its ability to induce apoptosis in endothelial cells and cardiomyocytes by activation of p53 protein and reactive oxygen species. We evaluated the potential roles of H(2)O(2) and p53 in DOX-induced apoptosis in normal bovine aortic endothelial cells and adult rat cardiomyocytes and in tumor cell lines PA-1 (human ovarian teratocarcinoma) and MCF-7 (human breast adenocarcinoma).

Non-heme iron protein: a potential target of nitric oxide in acute cardiac allograft rejection.

We examined iron nitrosylation of non-heme protein and enzymatic activity of the Fe-S cluster protein, aconitase, in acute cardiac allograft rejection. Heterotopic transplantation of donor hearts was performed in histocompatibility matched (isografts: Lewis --> Lewis) and mismatched (allografts: Wistar-Furth --> Lewis) rats. On postoperative days (POD) 4-6, Western blot analysis and immunohistochemistry revealed inducible nitric-oxide synthase (iNOS) protein in allografts but not isografts.

Paradoxical effects of metalloporphyrins on doxorubicin-induced apoptosis: scavenging of reactive oxygen species versus induction of heme oxygenase-1.

The cytoprotective effects of redox-active metalloporphyrins (e.g., FeTBAP and MnTBAP) were generally attributed to their ability to scavenge reactive oxygen and nitrogen species.

Doxorubicin-induced apoptosis: implications in cardiotoxicity.

In this review, we discuss the role of nitric oxide synthase in doxorubicin (DOX)-induced cardiomyopathy, a prominent side effect of DOX chemotherapy in cancer patients. It is becoming increasingly clear that apoptosis of myocardial cells plays a critical role in the onset of cardiomyopathy. DOX exposure to endothelial cells and cardiomyocytes caused apoptotic cell death at sub-micromolar concentrations.

Activation of nuclear factor-kappaB during doxorubicin-induced apoptosis in endothelial cells and myocytes is pro-apoptotic: the role of hydrogen peroxide.

Doxorubicin (DOX) is a widely used anti-tumour drug. Cardiotoxicity is a major toxic side effect of DOX therapy. Although recent studies implicated an apoptotic pathway in DOX-induced cardiotoxicity, the mechanism of DOX-induced apoptosis remains unclear.

Bicarbonate exacerbates oxidative injury induced by antitumor antibiotic doxorubicin in cardiomyocytes.

Doxorubicin, a broad-spectrum antitumor antibiotic, causes dose-dependent cardiomyopathy and heart failure. Although the exact molecular mechanisms of cardiotoxicity are not well established, oxidative mechanisms involving doxorubicin-induced superoxide anion production have been proposed. In this study, we show that bicarbonate, a physiologically relevant tissue component, greatly amplified doxorubicin-induced cardiomyocyte injury.

Modification of creatine kinase by S-nitrosothiols: S-nitrosation vs. S-thiolation.

Creatine kinase is reversibly inhibited by incubation with S-nitrosothiols. Loss of enzyme activity is associated with the depletion of 5,5'-dithiobis (2-nitrobenzoic acid)-accessible thiol groups, and is not due to nitric oxide release from RSNO. Full enzymatic activity and protein thiol content are restored by incubation of the S-nitrosothiol-modified protein with glutathione.

Doxorubicin-induced apoptosis in endothelial cells and cardiomyocytes is ameliorated by nitrone spin traps and ebselen. Role of reactive oxygen and nitrogen species.

Doxorubicin (DOX) is a broad spectrum anthracycline antibiotic used to treat a variety of cancers. Redox activation of DOX to form reactive oxygen species has been implicated in DOX-induced cardiotoxicity. In this work we investigated DOX-induced apoptosis in cultured bovine aortic endothelial cells and cardiomyocytes isolated from adult rat heart.

Resistance to myocardial ischemia in five rat strains: is there a genetic component of cardioprotection?

There is a need to develop new and more consistent animal models of cardioprotection. Traditionally, outbred dogs, rabbits, and rats have been studied. We determined resistance to ischemia in isolated hearts from inbred strains of rats.

Cell-permeable superoxide dismutase and glutathione peroxidase mimetics afford superior protection against doxorubicin-induced cardiotoxicity: the role of reactive oxygen and nitrogen intermediates.

The use of the potent antitumor antibiotic doxorubicin (DOX) is hampered because of its severe cardiac toxicity that leads to the development of cardiomyopathy and heart failure. In this study, we have developed a cell culture model for DOX-induced myocardial injury using primary adult rat cardiomyocytes that were cultured in serum-free medium and exposed to 1 to 40 microM DOX. DOX caused a dose-dependent release of sarcosolic enzyme lactate dehydrogenase (LDH) from cultured myocytes.

The peroxynitrite generator, SIN-1, becomes a nitric oxide donor in the presence of electron acceptors.

SIN-1 has been used, in vitro, to simultaneously generate nitric oxide (*NO) and superoxide (O*-2). However, the pharmacological activity of SIN-1 resembles that of a *NO donor. SIN-1 decays by a three-step mechanism.

Rapid and irreversible inhibition of creatine kinase by peroxynitrite.

We examined the ability of peroxynitrite and other .NO-derived oxidants to inhibit creatine kinase (CK). Peroxynitrite potently inhibited CK activity and depleted protein thiols.

S-Nitrosoglutathione as a substrate for gamma-glutamyl transpeptidase.

S-Nitrosoglutathione (GSNO) has been used as a nitric oxide (.NO) donor compound and has also been postulated to be involved in the transport of .NO in vivo.