title: Role of Peroxynitrite-Induced Activation of Poly(ADP-Ribose) Polymerase (PARP) in Circulatory Shock and Related Pathological Conditions.
abstract: Peroxynitrite is a powerful oxidant, formed from the reaction of nitric oxide and superoxide. It is known to interact and modify different biological molecules such as DNA, lipids and proteins leading to alterations in their structure and functions. These events elicit various cellular responses, including cell signaling, causing oxidative damage and committing cells to apoptosis or necrosis. This review discusses nitrosative stress-induced modification in the DNA molecule that results in the formation of 8-nitroguanine and 8-oxoguanine, and its role in disease conditions. Different approaches of cell death, such as necrosis and apoptosis, are modulated by cellular high-energy species, such as ATP and NAD+. High concentrations of peroxynitrite are known to cause necrosis, whereas low concentrations lead to apoptosis. Any damage to DNA activates cellular DNA repair machinery, like poly(ADP-ribose) polymerase (PARP). PARP-1, an isoform of PARP, is a DNA nick-sensing enzyme that becomes activated upon sensing DNA breakage and triggers the cleavage of NAD+into nicotinamide and ADP-ribose and polymerizes the latter on nuclear acceptor proteins. Peroxynitrite-induced hyperactivation of PARP causes depletion of NAD+and ATP culminating cell dysfunction, necrosis or apoptosis. This mechanistic pathway is implicated in the pathogenesis of a variety of diseases, including circulatory shock (which is characterized by cellular hypoxia triggered by systemic altered perfusion and tissue oxygen utilization leading end-organ dysfunction), sepsis and inflammation, injuries of the lung and the intestine. The cytotoxic effects of peroxynitrite centering on the participation of PARP-1 and ADP-ribose in previously stated diseases have also been discussed in this review.
authors.affiliation: Department of Biochemistry, J. N. Medical College, Aligarh Muslim University, Aligarh, UP, 202002, India.
authors.forename: Badar Ul
authors.initials: BU
authors.lastname: Islam
authors.affiliation: Department of Biochemistry, J. N. Medical College, Aligarh Muslim University, Aligarh, UP, 202002, India.
authors.forename: Safia
authors.initials: S
authors.lastname: Habib
authors.affiliation: Kothiwal Dental College and Research Center, Moradabad, UP, India.
authors.forename: Syed Amaan
authors.initials: SA
authors.lastname: Ali
authors.affiliation: Department of Biochemistry, J. N. Medical College, Aligarh Muslim University, Aligarh, UP, 202002, India.
authors.lastname: Moinuddin
authors.affiliation: Department of Biochemistry, J. N. Medical College, Aligarh Muslim University, Aligarh, UP, 202002, India. asifali_amu@rediffmail.com.
authors.forename: Asif
authors.initials: A
authors.lastname: Ali
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology; D016923:Cell Death / Q000502:physiology; D004249:DNA Damage / Q000502:physiology; D004790:Enzyme Induction / Q000502:physiology; D006801:Humans; D018384:Oxidative Stress / Q000502:physiology; D030421:Peroxynitrous Acid / Q000502:physiology*; D011065:Poly(ADP-ribose) Polymerases / Q000096:biosynthesis*; D012769:Shock / Q000378:metabolism* / Q000473:pathology*
chemical_list: D030421:Peroxynitrous Acid; D011065:Poly(ADP-ribose) Polymerases
keywords: Circulatory shock; DNA; Peroxynitrite; Poly(ADP-ribose) polymerase-1; Sepsis