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

Pál Pacher, Csaba Szabo

Research output: Contribution to journalArticle

199 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)235-260
Number of pages26
JournalCardiovascular Drug Reviews
Volume25
Issue number3
DOIs
StatePublished - Sep 2007
Externally publishedYes

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Myocardial Reperfusion Injury
Cardiovascular Diseases
Diabetes Complications
Reperfusion Injury
Cardiomyopathies
Cardiac Myocytes
Hypertrophy
Myocardial Ischemia
Shock
Atherosclerosis
Endothelial Cells
Heart Failure
Reactive Nitrogen Species
Purines
Enzyme Activation
Wounds and Injuries
Polyamines
Therapeutic Uses
Glycolysis
Electron Transport

Keywords

  • Angiogenesis
  • Apoptosis
  • Cardiomyopathy
  • Diabetes
  • DNA repair
  • Heart failure
  • Inflammation
  • Necrosis
  • Nitric oxide
  • Peroxynitrite
  • Poly(ADP-ribose) polymerase
  • Vascular remodeling

ASJC Scopus subject areas

  • Pharmacology
  • Cardiology and Cardiovascular Medicine

Cite this

Role of poly(ADP-ribose) polymerase 1 (PARP-1) in cardiovascular diseases : The therapeutic potential of PARP inhibitors. / Pacher, Pál; Szabo, Csaba.

In: Cardiovascular Drug Reviews, Vol. 25, No. 3, 09.2007, p. 235-260.

Research output: Contribution to journalArticle

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