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Poly (ADP-ribose) polymerase activation and circulatory shock
1Department of Surgery, UMD NJ-New Jersey Medical School, Newark, NJ 07103, USA.
Novartis Foundation Symposium
|March 27, 2007
Summary
Poly (ADP-ribose) polymerase (PARP) activation contributes to sepsis-induced cardiac dysfunction and hemodynamic failure. PARP inhibition shows promise, but protective effects may differ between sexes due to estrogen.
Area of Science:
- Biochemistry
- Cellular Biology
- Pathophysiology
Background:
- Sepsis elevates reactive oxidant species, inducing oxidative and nitrosative stress.
- This stress activates poly (ADP-ribose) polymerase (PARP), depleting NAD+ and impairing cellular energy production (ATP formation).
- PARP activation also promotes inflammation via NF-kappaB, MAP kinase, and AP-1 pathways.
Purpose of the Study:
- To investigate the role of PARP activation in sepsis-induced cardiac dysfunction and hemodynamic failure.
- To explore the potential of PARP inhibition as a therapeutic strategy in sepsis.
Main Methods:
- Review of preclinical studies in rodent and large animal models of septic and hemorrhagic shock.
- Analysis of a retrospective study of 25 septic patients, examining plasma troponin levels, myocardial damage, and immunohistochemical staining for poly (ADP-ribose) (PAR).
Main Results:
- Preclinical studies show beneficial effects of PARP inhibition or deficiency in shock models.
- Septic patients exhibited increased PAR staining in myocardial tissue, correlating with troponin I levels and LVSSW.
- Myocardial damage, inflammation, and mitochondrial derangement were observed in non-surviving septic patients.
Conclusions:
- PARP activation contributes to cardiac depression and hemodynamic failure in severe sepsis.
- PARP inhibition may be a viable therapeutic approach, though gender-specific effects warrant further investigation.
- Estrogen may play a role in the observed gender difference in PARP inhibitor efficacy.
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