Poly(ADP-ribose) polymerase-1 inhibition increases expression of heat shock proteins and attenuates heat stroke-induced liver injury.
OBJECTIVE
Heat stroke is a life-threatening illness characterized by an increased core body temperature as a result of exposure to high ambient temperature. Despite advances in supportive care, heat stroke is often fatal, and no specific and effective therapies exist. The pathophysiological responses to heat stroke involve a systemic inflammatory response and a disseminated intravascular coagulation in the host, which lead to a multiorgan dysfunction syndrome. Poly(ADP-ribose) polymerase-1 (PARP-1) is a nuclear DNA-binding protein that has been shown to play a relevant role in cell necrosis and organ failure in various diseases associated with inflammation. Therefore, we set out to investigate whether inhibition of PARP activity might affect the heat stroke-induced injury.


METHODS
Controlled animal study.


METHODS
Research laboratory of an academic institution.


METHODS
PARP-1-deficient mice (Parp-1(-/-)) and wild-type mice (C57BL/6J).


METHODS
Wild-type mice untreated or treated with either PJ34 or 3-AB, two generic PARP inhibitors, and Parp-1(-/-) mice were subjected to heat exposure as a model to study heat stroke.


RESULTS
We measured rectal temperature, serum interleukin-1beta and interleukin-6, liver histology, and heat shock proteins expression. We found that the heat stroke-induced injury was attenuated in mice lacking PARP-1 and was markedly reduced in wild-type mice treated with PARP inhibitors. Interestingly, heat-induced expression of heat shock proteins 27 and 70 was boosted after PARP inhibition. Indeed, PARP inhibition increased expression of heat shock proteins 27 and 70 even in the absence of heat exposure. Accordingly, PARP inhibition increased thermal tolerance that may contribute to attenuate the clinical effects of heat stroke, resulting in increased survival.


CONCLUSIONS
Our results find a new protective function of PARP inhibitors and support their potential therapeutic application in the treatment of heat stroke.
Mota
Rubén A
RA
Department of Surgery, Hospital Virgen de la Arrixaca, Ciberehd, Murcia, Spain.
Hernández-Espinosa
David
D
Galbis-Martinez
Lilian
L
Ordoñez
Adriana
A
Miñano
Antonia
A
Parrilla
Pascual
P
Vicente
Vicente
V
Corral
Javier
J
Yélamos
José
J
D000818:Animals; D016207:Cytokines / Q000378:metabolism; D018883:Heat Stroke / Q000150:complications* / Q000378:metabolism / Q000473:pathology; D006360:Heat-Shock Proteins / Q000378:metabolism; D006400:Hematocrit; D008107:Liver Diseases / Q000209:etiology* / Q000378:metabolism / Q000517:prevention & control*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010616:Phenanthrenes / Q000627:therapeutic use*; D000071137:Poly (ADP-Ribose) Polymerase-1; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; D011065:Poly(ADP-ribose) Polymerases / Q000502:physiology; D015431:Weight Loss
D016207:Cytokines; D006360:Heat-Shock Proteins; C434926:N-(oxo-5,6-dihydrophenanthridin-2-yl)-N,N-dimethylacetamide hydrochloride; D010616:Phenanthrenes; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; C499321:Parp1 protein, mouse; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases