Activation of Poly(ADP-Ribose) Polymerase Contributes to Development of Doxorubicin-Induced Heart Failure

Abstract

Activation of the nuclear enzyme poly(ADP-ribose) polymerase (PARP) by oxidant-mediated DNA damage is an important pathway of cell dysfunction and tissue injury in conditions associated with oxidative stress. Increased oxidative stress is a major factor implicated in the cardiotoxicity of doxorubicin (DOX), a widely used antitumor anthracycline antibiotic. Thus, we hypothesized that the activation of PARP may contribute to the DOX-induced cardiotoxicity. Using a dual approach of PARP-1 suppression, by genetic deletion or pharmacological inhibition with the phenanthridinone PARP inhibitor PJ34, we now demonstrate the role of PARP in the development of cardiac dysfunction induced by DOX. PARP-1ϩ/ϩ and PARP-1Ϫ/Ϫ mice received a single injection of DOX (25 mg/kg i.p). Five days after DOX administration, left ventricular performance was significantly depressed in PARP-1ϩ/ϩ mice, but only to a smaller extent in PARP-1Ϫ/Ϫ ones. Similar experiments were conducted in BALB/c mice treated with PJ34 or vehicle. Treatment with a PJ34 significantly improved cardiac dysfunction and increased the survival of the animals. In addition PJ34 significantly reduced the DOX-induced increase in the serum lactate dehydrogenase and creatine kinase activities but not metalloproteinase activation in the heart. Thus, PARP activation contributes to the cardiotoxicity of DOX. PARP inhibitors may exert protective effects against the development of severe cardiac complications associated with the DOX treatment.Poly(ADP-ribose) polymerase (PARP), also known as poly-(ADP ribose) synthetase (PARS), is an abundant nuclear enzyme of eukaryotic cells. When activated by DNA singlestrand breaks, PARP initiates an energy-consuming cycle by transferring ADP ribose units from NAD ϩ to nuclear proteins. This process results in rapid depletion of the intracellular NAD ϩ and ATP pools, slowing the rate of glycolysis and mitochondrial respiration and eventually leading to cellular dysfunction and death (Eliasson et al., 1997;Szabó et al., 1997;Zingarelli et al., 1998;Burkart et al., 1999;Szabó, 2000). Overactivation of PARP represents an important mechanism of tissue damage in various pathological conditions associated with oxidant stress, including myocardial reperfusion injury (Zingarelli et al., 1998), stroke (Eliasson et al., 1997), circulatory shock Oliver et al., 1999;Liaudet et al., 2000), and autoimmune ␤-cell destruction (Burkart et al., 1999;Pieper et al., 1999). Activation of PARP also contributes to the development of cardiovascular dysfunction in diabetes (Soriano et al., 2001a,b;Pacher et al., 2002). Doxorubicin (DOX; Adriamycin; Pharmacia & Upjohn, Peapack, NJ) is a broad-spectrum antitumor anthracycline antibiotic that is commonly used to treat a variety of cancers, including severe leukemias, lymphomas, and solid tumors (Blum and Carter, 1974;Young et al., 1981;Singal et al., 1987;Hortobagyi, 1997;Singal and Iliskovic, 1998). However, the clinical use of DOX is limited because of its serious cardiotoxicity, which leads to irreversible...

Cannabidiol Protects against Doxorubicin-Induced Cardiomyopathy by Modulating Mitochondrial Function and Biogenesis

“…Indeed, both neutralization of peroxynitrite by peroxynitrite decomposition catalysts or inhibition of iNOS or PARP is protective against DOX-induced cardiotoxicity in murine models of DOX-induced cardiomyopathies. (4,5,13). DOX via increased generation of reactive oxygen and nitrogen species also leads to activation of MMP enzymes (31), which in turn promotes pathological remodeling (4,14,32,33).…”

“…The mechanism of DOX's cardiotoxicity is complex and may involve oxidative (2,3), nitrosative and nitrative stress (4,5), mitochondrial dysfunction/ toxicity (1,(6)(7)(8), dysregulation of various metabolic (9) and lipid signaling pathways (10)(11)(12), activation of various stress kinases and cell death mechanisms (both apoptotic and necrotic) (13), triggering of secondary inflammation and remodeling (14), eventually culminating in cardiac dysfunction and heart failure (1,15).…”

Potent Metalloporphyrin Peroxynitrite Decomposition Catalyst Protects Against the Development of Doxorubicin-Induced Cardiac Dysfunction

“…10,14 In a separate set of experiments, DOX was injected in 3 equal doses of 9 mg · kg Ϫ1 · d Ϫ1 on days 1, 10, and 20, and hemodynamics was measured on day 25. Treatment with FeCl tetrakis-2-(triethylene glycol monomethyl ether) pyridyl porphyrin (FP15) (0.03 to 1 mg · kg Ϫ1 · d Ϫ1 PO), aminoguanidine (AG; 50 and 100 mg · kg Ϫ1 · d Ϫ1 IP), or N-nitro-L-arginine methyl ester (L-NAME, 10 and 20 mg · kg Ϫ1 · d Ϫ1 IP) started 2, 24, and 24 hours before DOX injection and continued until hemodynamic measurements were completed or survival studies were terminated.…”

“…A microtip pressure-volume catheter (SPR-839; Millar Instruments) was inserted into the right carotid artery and advanced into the LV under pressure control as described. 14,15 After stabilization for 20 minutes, the signals were recorded continuously with an ARIA pressure-volume conductance system (Millar Instruments) coupled with a Powerlab/4SP A/D converter (AD Instruments), stored, and displayed on a personal computer. The heart rate, maximal LV systolic (LVSP) and end-diastolic (LVEDP) pressures, maximal slope of systolic pressure increment (ϩdP/dt) and diastolic pressure decrement (ϪdP/dt), stroke volume (SV), stroke work (SW), ejection fraction, and cardiac output (CaO) were calculated and corrected according to in vitro and in vivo volume calibrations with a cardiac pressure-volume analysis program (PVAN2.9; Millar Instruments).…”

Amidization of doxorubicin alleviates doxorubicin-induced contractile dysfunction and reduced survival in murine cardiomyocytes

“…Meanwhile, direct measurement of ROS generation revealed reduced ROS generating capacity in amidized doxorubicin, supporting the notion of ROS-induced oxidative damage as a major culprit factor for doxorubicin-induced cardiomyopathy (Olson and Mushlin 1990). Recent evidence has indicated that peroxynitrite formation resulted from dysregulated nitric oxide and activation of the nuclear enzyme poly(ADP-ribose) polymerase (PARP) by oxidant-mediated DNA damage may contribute to cardiotoxicity of doxorubicin (Pacher et al 2002;Pacher et al 2003;Pacher et al 2007). Our earlier evidence suggested that the doxorubicin-induced prolongation of TR 90 may be underscored by prolongation in intracellular Ca 2+ transient clearance (Wold et al 2005).…”