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PMID: 17919258 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, N.I.H., Intramural Review

Role of poly(ADP-ribose) polymerase 1 (PARP-1) in cardiovascular diseases: the therapeutic potential of PARP inhibitors.

Cardiovascular drug reviews ·Vol. 25 ·No. 3 ·2007-00-00 ·Pages 235-60

Pacher P, Szabó C

Abstract

Accumulating evidence suggests that the reactive oxygen and nitrogen species are generated in cardiomyocytes and endothelial cells during myocardial ischemia/reperfusion injury, various forms of heart failure or cardiomyopathies, circulatory shock, cardiovascular aging, diabetic complications, myocardial hypertrophy, atherosclerosis, and vascular remodeling following injury. These reactive species induce oxidative DNA damage and consequent activation of the nuclear enzyme poly(ADP-ribose) polymerase 1 (PARP-1), the most abundant isoform of the PARP enzyme family. PARP overactivation, on the one hand, depletes its substrate, NAD+, slowing the rate of glycolysis, electron transport, and ATP formation, eventually leading to the functional impairment or death of the endothelial cells and cardiomyocytes. On the other hand, PARP activation modulates important inflammatory pathways, and PARP-1 activity can also be modulated by several endogenous factors such as various kinases, purines, vitamin D, thyroid hormones, polyamines, and estrogens, just to mention a few. Recent studies have demonstrated that pharmacological inhibition of PARP provides significant benefits in animal models of cardiovascular disorders, and novel PARP inhibitors have entered clinical development for various cardiovascular indications. Because PARP inhibitors can enhance the effect of anticancer drugs and decrease angiogenesis, their therapeutic potential is also being explored for cancer treatment. This review discusses the therapeutic effects of PARP inhibitors in myocardial ischemia/reperfusion injury, various forms of heart failure, cardiomyopathies, circulatory shock, cardiovascular aging, diabetic cardiovascular complications, myocardial hypertrophy, atherosclerosis, vascular remodeling following injury, angiogenesis, and also summarizes our knowledge obtained from the use of PARP-1 knockout mice in the various preclinical models of cardiovascular diseases.

MeSH Terms
Animals Cardiovascular Diseases/drug therapy,enzymology,pathology Enzyme Inhibitors/chemistry,pharmacology,therapeutic use Humans Models, Biological Molecular Structure Poly (ADP-Ribose) Polymerase-1 Poly(ADP-ribose) Polymerase Inhibitors Poly(ADP-ribose) Polymerases/metabolism
Chemicals
Enzyme Inhibitors Poly(ADP-ribose) Polymerase Inhibitors PARP1 protein, human Poly (ADP-Ribose) Polymerase-1 Poly(ADP-ribose) Polymerases
Authors & Affiliations
2 authors, click to expand affiliations / ORCID
Pacher Pál
Section on Oxidative Stress and Tissue Injury, Laboratory of Physiological Studies, National Institutes of Health, NIAAA, Bethesda MD 20892-9413, USA. [email protected]
Szabó Csaba
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Article Info
Journal
Cardiovascular drug reviews
Abbr.
Cardiovasc Drug Rev
ISSN
0897-5957
DOI
10.1111/j.1527-3466.2007.00018.x
Email
[email protected]
Published
2007-00-00
Pages
235-60
Language
English
Region
United States
NLM ID
9006912
PMCID
PMC2225457
Subset
IM
Grants
NIGMS NIH HHS · R01 GM060915 · United States
NIGMS NIH HHS · R01 GM060915-01 · United States
Intramural NIH HHS · Z01 AA000375-02 · United States
External Links
PubMed source DOI: 10.1111/j.1527-3466.2007.00018.x PMC Full Text
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