PARP as a drug target for the therapy of diabetic cardiovascular dysfunction

Research output: Contribution to journalArticle

50 Citations (Scopus)

Abstract

Poly(ADP-ribose) polymerase-1 (PARP-1) is a member of the PARP enzyme family consisting of PARP-1 and a growing family of additional, novel poly(ADP-ribosylating) enzymes. PARP-1 is one of the most abundant nuclear proteins, and it functions as a DNA nick sensor enzyme. Upon binding to DNA breaks, activated PARP cleaves NAD+ into nicotinamide and ADP-ribose and polymerizes the latter onto nuclear acceptor proteins including histones, transcription factors and PARP itself. Over-activation of PARP in response to oxidant- and free radical-mediated excessive DNA single strand breaks promotes cell dysfunction and necrotic-type cell death in a variety of pathophysiological conditions. Emerging data indicate that high circulating glucose in diabetes mellitus is able to induce free radical and oxidant generation in the cardiovascular system with the concomitant activation of PARP. This process results in acute loss of the ability of the endothelium to release nitric oxide (endothelial dysfunction) and leads to a severe functional impairment of the heart (diabetic cardiomyopathy). Accordingly, pharmacological inhibition of PARP protects against diabetic cardiovascular dysfunction. Surprisingly, PARP inhibition not only prevents the development of diabetic endothelial dysfunction, but also restores normal vascular function in established diabetes. In addition to the direct cytotoxic pathway regulated by DNA injury and PARP activation, PARP also modulates the course of cardiovascular inflammation and injury by regulating the activation of NF-κB, and the expression of a number of proinflammatory genes. The research into the role of PARP in diabetic cardiovascular injury is now supported by novel tools, such as new classes of potent inhibitors of PARP, as well as genetically engineered animals lacking the gene for PARP. Inhibitors of PARP may become useful in the experimental therapy of diabetic vascular complications.

Original languageEnglish (US)
Pages (from-to)197-205
Number of pages9
JournalDrug News and Perspectives
Volume15
Issue number4
DOIs
StatePublished - 2002
Externally publishedYes

Fingerprint

Single-Stranded DNA Breaks
Nuclear Proteins
Oxidants
Drug Therapy
Free Radicals
Enzymes
Diabetic Cardiomyopathies
Adenosine Diphosphate Ribose
Diabetic Angiopathies
Investigational Therapies
Genetically Modified Animals
DNA Breaks
Wounds and Injuries
Cardiovascular System
NAD
Histones
Adenosine Diphosphate
Genes
DNA Damage
Endothelium

ASJC Scopus subject areas

  • Pharmacology

Cite this

PARP as a drug target for the therapy of diabetic cardiovascular dysfunction. / Szabo, Csaba.

In: Drug News and Perspectives, Vol. 15, No. 4, 2002, p. 197-205.

Research output: Contribution to journalArticle

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