Deoxyribonucleic acid damage/repairproteins are elevated in the failing human myocardium due to idiopathic dilated cardiomyopathy

Bartúnek, Jozef; Vanderheyden, Marc; Knaapen, Michiel; Tack, W.; Kockx, Mark; Goethals, Marc

doi:10.1016/s0735-1097(02)02122-8

Cited by 41 publications

(38 citation statements)

References 31 publications

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“…Our data support many previous studies where cell oxidative/nitrosative stress was shown to be involved in the development of cardiac hypertrophy (reviewed in Ref. 21) and in many other reports where failing hearts were found to be associated with increased activity of the PARP enzyme (1,24,32). These results strengthen the notion that PARP inhibition as monotherapy, or as a combination therapy that includes activation of the Sir2␣, may represent a novel approach for the management of heart failure.…”

Section: Discussionsupporting

confidence: 91%

Poly(ADP-ribose) polymerase-1-deficient mice are protected from angiotensin II-induced cardiac hypertrophy

Pillai¹,

Gupta²,

Rajamohan³

et al. 2006

American Journal of Physiology-Heart and Circulatory Physiology

100

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-(ADP-ribose) polymerase-1-deficient mice are protected from angiotensin II-induced cardiac hypertrophy. Am J Physiol Heart Circ Physiol 291: H1545-H1553, 2006. First published April 21, 2006 doi:10.1152/ajpheart.01124.2005.-Poly(ADP-ribose) polymerase-1 (PARP), a chromatin-bound enzyme, is activated by cell oxidative stress. Because oxidative stress is also considered a main component of angiotensin II-mediated cell signaling, it was postulated that PARP could be a downstream target of angiotensin II-induced signaling leading to cardiac hypertrophy. To determine a role of PARP in angiotensin II-induced hypertrophy, we infused angiotensin II into wild-type (PARP ϩ/ϩ ) and PARP-deficient mice. Angiotensin II infusion significantly increased heart weight-totibia length ratio, myocyte cross-sectional area, and interstitial fibrosis in PARP ϩ/ϩ but not in PARP Ϫ/Ϫ mice. To confirm these results, we analyzed the effect of angiotensin II in primary cultures of cardiomyocytes. When compared with PARP Ϫ/Ϫ cardiomyocytes, angiotensin II (1 M) treatment significantly increased protein synthesis in PARP ϩ/ϩ myocytes, as measured by 3 Hleucine incorporation into total cell protein. Angiotensin II-mediated hypertrophy of myocytes was accompanied with increased poly-ADP-ribosylation of nuclear proteins and depletion of cellular NAD content. When cells were treated with cell death-inducing doses of angiotensin II (10 -20 M), robust myocyte cell death was observed in PARP ϩ/ϩ but not in PARP Ϫ/Ϫ myocytes. This type of cell death was blocked by repletion of cellular NAD levels as well as by activation of the longevity factor Sir2␣ deacetylase, indicating that PARP induction and subsequent depletion of NAD levels are the sequence of events causing angiotensin II-mediated cardiomyocyte cell death. In conclusion, these results demonstrate that PARP is a nuclear integrator of angiotensin II-mediated cell signaling contributing to cardiac hypertrophy and suggest that this could be a novel therapeutic target for the management of heart failure. heart failure; oxidative-stress signaling IN SETTINGS OF sustained hemodynamic overload, myocardium undergoes a growth response, termed as cardiac hypertrophy. This process is characterized by an increase in myocyte cell size and alterations in expression of contractile and Ca 2ϩ -handling proteins. Cardiac hypertrophy initially develops as an adaptive response; however, if remained unchecked, this eventually progresses to ventricular dilation and pump dysfunction (12). At the biochemical level, many hypertrophy agonists have been identified; among them, angiotensin II has been established as a most potent stimulator of cardiac hypertrophy. Multiple signaling pathways that regulate angiotensin II-mediated cardiac hypertrophy response have been also identified; these include activation of PKC, MAPKs, and the production of reactive oxygen and nitrogen species (30). However, the downstream targets and nuclear integrators of angiotensin II-mediated cardiac growth response are not yet understood.Po...

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Section: Discussionsupporting

confidence: 91%

Poly(ADP-ribose) polymerase-1-deficient mice are protected from angiotensin II-induced cardiac hypertrophy

Pillai¹,

Gupta²,

Rajamohan³

et al. 2006

American Journal of Physiology-Heart and Circulatory Physiology

100

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“…15,16 These DNA repair enzymes, PCNA and Ref-1, were recently reported to be increased in the nucleus of myocytes of hearts with DCM. 17 In the present study, strong correlations were noted between expressions of PCNA, Ref-1, and 8-OHdG, suggesting that oxidative DNA damage might contribute to increased DNA repair.…”

Section: Discussionsupporting

confidence: 58%

Nuclear Hypertrophy Reflects Increased Biosynthetic Activities in Myocytes of Human Hypertrophic Hearts

Koda

Takemura

Okada

et al. 2006

Circ J

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n response to various stresses, cardiac myocytes present phenotypic alterations of the cytoplasm, such as increased cell volume, increased fraction of subcellular organelles in contrast to decreased fractions of myofilaments, mitochondriosis, and intracytoplasmic vacuoles. 1,2 Nuclear structure is markedly altered as well. The nuclear change has been well characterized as "hypertrophied nucleus" by the morphological hallmarks of severe crenation of the nuclear membrane (bizarre shape) and widespread clumping of chromatin. [3][4][5] However, the significance of such dramatic alteration of the nuclear phenotype in hypertrophic hearts is largely unknown. We previously reported that hypertrophied nuclei in the myocytes of human hearts with dilated cardiomyopathy (DCM) were accompanied by increased activity of DNA repair/synthesis. 6 Scholz et al speculated that the nuclear abnormalities might be the primary event in the pathogenesis of DCM and that they might lead to a reduced transcriptional rate, which most probably was the cause of the lack of myofilaments and other degenerative changes. 7 However, the molecular biological alterations are largely unknown in the hypertrophied nucleus of various hypertrophic hearts. We hypothesize that such a nuclear phenotype change is associated with various molecular biological alterations occurring in myocyte nuclei of pathologic hearts, which may also be related to cardiac functional alterations. Thus, the major aim of the present study was to use endomyocardial biopsy specimens from hypertrophic hearts of various etiologies to examine linkages between the structural and molecular biological alterations of the hypertrophied nuclei of cardiac myocytes of human hypertrophic hearts. Methods Patients and Endomyocardial BiopsiesThis study was approved by the Institutional Research Committee. A total of 93 patients with hypertrophic hearts were studied (Table 1): DCM (n=23); postmyocarditis (n=13); hypertrophic cardiomyopathy (HCM, n=21); apical hypertrophic cardiomyopathy (APH, n=11); hypertensive heart disease (HHD, n=11); 14 nonhypertrophic hearts served as controls. There were 67 males and 26 females with a mean age of 58±13 years. Echocardiography, cardiac catheterization, and coronary angiography were performed and left ventricular (LV) endomyocardial biopsies were obtained. Measurements included by echocardiography, LV mass index (LVMI); interventricular septal thickness, and LV posterior wall thickness, and by cardiac catheterization, LV end-diastolic volume index, LV ejection fraction (LVEF), and LV end-diastolic pressure. Each endomyocardial biopsy was originally performed for differentiation between primary and secondary myocardial diseases. The Background The nucleus of the myocytes in human hypertrophic hearts is characterized by its bizarre shape and widespread clumping of chromatin. The functional significance has not been determined. Methods and ResultsLeft ventricular (LV) endomyocardial biopsies obtained from patients with dilated cardiomyopathy (DCM, n=23), postmy...

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“…The NO-mediated increase in DNA-PKcs pathway not only plays an important role in tumour DNA repair [51], but may also play an important role in other tissue damage processes which involve NOmediated stress [52], [53]. For example, failing myocardium, (advanced heart failure due to idiopathic dilated cardiomyopathy) undergoes active DNA repair, where DNA-PKcs expression is strongly correlated with iNOS expression (r=0.53, p < 0.01) [53].…”

Section: No and Tumour Cell Angiogenesismentioning

confidence: 99%

“…For example, failing myocardium, (advanced heart failure due to idiopathic dilated cardiomyopathy) undergoes active DNA repair, where DNA-PKcs expression is strongly correlated with iNOS expression (r=0.53, p < 0.01) [53]. Given the fact that one of the major substrates of DNA-PKcs is p53 [54] and DNA-PKcs itself is subjected to ADP-ribosylation by PARP, it is possible that NO-mediated DNA damage and repair could play a significant role in tumour development (Fig 3).…”

Section: No and Tumour Cell Angiogenesismentioning

confidence: 99%

The role of nitric oxide in cancer

Liu

Loizidou³

et al. 2002

Cell Res

694

500

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Nitric oxide (NO) is a pleiotropic regulator, critical to numerous biological processes, including vasodilatation, neurotransmission and macrophage-mediated immunity. The family of nitric oxide synthases (NOS) comprises inducible NOS (iNOS), endothelial NOS (eNOS), and neuronal NOS (nNOS). Interestingly, various studies have shown that all three isoforms can be involved in promoting or inhibiting the etiology of cancer. NOS activity has been detected in tumour cells of various histogenetic origins and has been associated with tumour grade, proliferation rate and expression of important signaling components associated with cancer development such as the oestrogen receptor. It appears that high levels of NOS expression (for example, generated by activated macrophages) may be cytostatic or cytotoxic for tumor cells, whereas low level activity can have the opposite effect and promote tumour growth. Paradoxically therefore, NO (and related reactive nitrogen species) may have both genotoxic and angiogenic properties. Increased NO-generation in a cell may select mutant p53 cells and contribute to tumour angiogenesis by upregulating VEGF. In addition, NO may modulate tumour DNA repair mechanisms by upregulating p53, poly(ADP-ribose) polymerase (PARP) and the DNA-dependent protein kinase (DNA-PK). An understanding at the molecular level of the role of NO in cancer will have profound therapeutic implications for the diagnosis and treatment of disease.

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Deoxyribonucleic acid damage/repairproteins are elevated in the failing human myocardium due to idiopathic dilated cardiomyopathy

Abstract: In this study, apoptosis could not be detected in the failing myocardium owing to idiopathic dilated cardiomyopathy. In contrast, failing myocardium was characterized by active DNA repair that was associated with elevated LV wall stress and activation of the inducible NO synthase.

Cited by 41 publications

References 31 publications

Poly(ADP-ribose) polymerase-1-deficient mice are protected from angiotensin II-induced cardiac hypertrophy

Poly(ADP-ribose) polymerase-1-deficient mice are protected from angiotensin II-induced cardiac hypertrophy

Nuclear Hypertrophy Reflects Increased Biosynthetic Activities in Myocytes of Human Hypertrophic Hearts

The role of nitric oxide in cancer

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