Immunomodulatory Effects of Poly(ADP-ribose) Polymerase Inhibition Contribute to Improved Cardiac Function and Survival During Acute Cardiac Rejection

Szabó, Gábor; Bährle, Susanne; Sivanandam, Vijayshankar; Stumpf, Nicole; Gerö, Domokos; Berger, Irina; Beller, Carsten J.; Hagl, S.; Szabó, Csaba; Dengler, Thomas J.

doi:10.1016/j.healun.2006.03.017

Cited by 12 publications

(8 citation statements)

References 22 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…The cardiac protective effect of PARP inhibitors was subsequently extended into various models of heart transplantation. Treatment of the recipients with PARP inhibitors resulted in improved myocardial contractility and longer survival time of the transplanted hearts (Fiorillo et al, 2002(Fiorillo et al, , 2003Szabó et al, 2002Szabó et al, , 2005Szabó et al, , 2006Liu et al, 2004;Gao et al, 2007). The mode of action of PARP inhibitors, as cardioprotective agents, appears to involve a combination of mechanisms.…”

Section: Discussionmentioning

confidence: 99%

Olaparib protects cardiomyocytes against oxidative stress and improves graft contractility during the early phase after heart transplantation in rats

Korkmaz‐Icöz

Szczesny

Marcatti

et al. 2017

British J Pharmacology

Self Cite

View full text Add to dashboard Cite

*Equally contributed. BACKGROUND AND PURPOSEOlaparib, rucaparib and niraparib, potent inhibitors of poly(ADP-ribose) polymerase (PARP) are approved as anti-cancer drugs in humans. Considering the previously demonstrated role of PARP in various forms of acute and chronic myocardial injury, we tested the effects of olaparib in in-vitro models of oxidative stress in cardiomyocytes, and in an in vivo model of cardiac transplantation. EXPERIMENTAL APPROACHH9c2-embryonic rat heart-derived myoblasts pretreated with vehicle or olaparib (10μM) were challenged with either hydrogen peroxide (H 2 O 2 ) or with glucose oxidase (GOx, which generates H 2 O 2 in the tissue culture medium). Cell viability assays (MTT, lactate dehydrogenase) and Western blotting for PARP and its product, PAR was performed. Heterotopic heart transplantation was performed in Lewis rats; recipients were treated either with vehicle or olaparib (10 mg kg -1 ). Left ventricular function of transplanted hearts was monitored via a Millar catheter. Multiple gene expression in the graft was measured by qPCR. KEY RESULTSOlaparib blocked autoPARylation of PARP1 and attenuated the rapid onset of death in H9c2 cells, induced by H 2 O 2 , but did not affect cell death following chronic, prolonged oxidative stress induced by GOx. In rats, after transplantation, left ventricular systolic and diastolic function were improved by olaparib. In the transplanted hearts, olaparib also reduced gene expression for c-jun, caspase-12, catalase, and NADPH oxidase-2. CONCLUSIONS AND IMPLICATIONSOlaparib protected cardiomyocytes against oxidative stress and improved graft contractility in a rat model of heart transplantation. These findings raise the possibility of repurposing this clinically approved oncology drug, to be used in heart transplantation. LINKED ARTICLES

show abstract

Section: Discussionmentioning

confidence: 99%

Olaparib protects cardiomyocytes against oxidative stress and improves graft contractility during the early phase after heart transplantation in rats

Korkmaz‐Icöz

Szczesny

Marcatti

et al. 2017

British J Pharmacology

Self Cite

View full text Add to dashboard Cite

show abstract

“…In these models, too, the efficacy of PARP inhibition proved substantial, as evidenced by improved contractility of the transplanted hearts, and by increased survival time of the transplanted heart (Szabo et al, 2002a; Fiorillo et al, 2002; Liu et al, 2004; Szabo et al, 2005; Farivar et al, 2005; Szabo et al, 2006a; Szabo et al, 2006b; Gao et al, 2007). In addition to rodent models, the cardioprotective effect of PARP inhibition has also been demonstrated in various large animal models.…”

Section: Beyond Anticancer Therapy: Stroke Circulatory Shock Carmentioning

confidence: 99%

Therapeutic applications of PARP inhibitors: Anticancer therapy and beyond

Curtin

Szabó

2013

Molecular Aspects of Medicine

327

286

View full text Add to dashboard Cite

The aim of this article is to describe the current and potential clinical translation of pharmacological inhibitors of poly(ADP-ribose) polymerase (PARP) for the therapy of various diseases. The first section of the present review summarizes the available preclinical and clinical data with PARP inhibitors in various forms of cancer. In this context, the role of PARP in single-strand DNA break repair is relevant, leading to replication-associated lesions that cannot be repaired if homologous recombination (HRR) repair is defective, and the synthetic lethality of PARP inhibitors in HRR-defective cancer. HRR defects are classically associated with BRCA1 and 2 mutations associated with familial breast and ovarian cancer, but there may be many other causes of HRR defects. Thus, PARP inhibitors may be the drugs of choice for BRCA mutant breast and ovarian cancers, and extend beyond these tumors if appropriate biomarkers can be developed to identify HRR defects. Multiple lines of preclinical data demonstrate that PARP inhibition increases cytotoxicity and tumor growth delay in combination with temozolomide, topoisomerase inhibitors and ionizing radiation. Both single agent and combination clinical trials are underway. The final part of the first section of the present review summarizes the current status of the various PARP inhibitors that are in various stages of clinical development. The second section of the present review summarizes the role of PARP in selected non-oncologic indications. In a number of severe, acute diseases (such as stroke, neurotrauma, circulatory shock and acute myocardial infarction) the clinical translatability of PARP inhibition is supported by multiple lines of preclinical data, as well as observational data demonstrating PARP activation in human tissue samples. In these disease indications, PARP overactivation due to oxidative and nitrative stress drives cell necrosis and pro-inflammatory gene expression, which contributes to disease pathology. Accordingly, multiple lines of preclinical data indicate the efficacy of PARP inhibitors to preserve viable tissue and to down-regulate inflammatory responses. As the clinical trials with PARP inhibitors in various forms of cancer progress, it is hoped that a second line of clinical investigations, aimed at testing of PARP inhibitors for various non-oncologic indications, will be initiated, as well.

show abstract

“…Dosing to achieve therapeutic INO-1001 drug levels was established previously [14]. Based on these results, mice were treated with 1 mg/kg body weight of the PARP inhibitor INO-1001 (n = 15), dissolved in 5% glucose, while the control group received 5% glucose solution (n = 15) by intraperitoneal injection daily for 10 weeks.…”

Section: Resultsmentioning

confidence: 99%

“…A previous study of our group shows that PARP inhibition with INO-1001 suppresses both alloantigen-dependent (MLR) and antigen-independent (PHA) T-cell proliferation [14]. In addition, previously it was shown that T cells are reduced in PARP inhibited mice[10].…”

Section: Discussionmentioning

confidence: 99%

PARP inhibition in atherosclerosis and its effects on dendritic cells, T cells and auto-antibody levels

et al. 2011

View full text Add to dashboard Cite

ObjectiveAtherosclerosis is a chronic inflammatory process. Poly(ADP-ribose) polymerase-1 (PARP), a nuclear enzyme linked to DNA repair, has been shown to be involved in atherogenesis; however, the effects on dendritic cells, T cells and serum auto-antibody levels are not fully understood.MethodsMale Apoe-/- mice on a western diet were treated with the PARP inhibitor 1NO-1001 (n = 15), while the control group (n = 15) received 5% glucose solution for 10 weeks.ResultsInhibition of PARP markedly reduced atherosclerotic lesion development (p = 0.001). Immunohistochemistry and mRNA analysis revealed a reduced inflammatory compound inside the lesion. Focusing on dendritic cells, INO-1001 reduced number of cells (p = 0.04), grade of activation, represented by I/12 (p = 0.04) and Cd83 (p = 0.03), and grade of attraction, represented by Mip3α (p = 0.02) in the plaque. Furthermore, INO-1001 decreased number of T lymphocyte (p = 0.003) in the lesion and grade of activation after stimulation with oxLDL in vitro. Moreover, serum IgM antibody levels to oxLDL were significantly lower in INO-1001 treated mice (p = 0.03).ConclusionsFunctional blockade of PARP by INO-1001 reduces atherosclerotic lesion development. The anti-atherogenic effect is beside already known mechanisms also moderated due to modulation of DC and T cell invasion and activation, DC attraction as well as IgM antibody levels to oxLDL.

show abstract

Immunomodulatory Effects of Poly(ADP-ribose) Polymerase Inhibition Contribute to Improved Cardiac Function and Survival During Acute Cardiac Rejection

Cited by 12 publications

References 22 publications

Olaparib protects cardiomyocytes against oxidative stress and improves graft contractility during the early phase after heart transplantation in rats

Olaparib protects cardiomyocytes against oxidative stress and improves graft contractility during the early phase after heart transplantation in rats

Therapeutic applications of PARP inhibitors: Anticancer therapy and beyond

PARP inhibition in atherosclerosis and its effects on dendritic cells, T cells and auto-antibody levels

Contact Info

Product

Resources

About