3.8 Review

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

期刊

CARDIOVASCULAR DRUG REVIEWS
卷 25, 期 3, 页码 235-260

出版社

WILEY
DOI: 10.1111/j.1527-3466.2007.00018.x

关键词

angiogenesis; apoptosis; cardiomyopathy; diabetes; DNA repair; heart failure; inflammation; necrosis; nitric oxide; peroxynitrite; poly(ADP-ribose) polymerase; vascular remodeling

资金

  1. NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES [R01GM060915] Funding Source: NIH RePORTER
  2. NATIONAL INSTITUTE ON ALCOHOL ABUSE AND ALCOHOLISM [Z01AA000375] Funding Source: NIH RePORTER
  3. Intramural NIH HHS [Z01 AA000375-02] Funding Source: Medline
  4. NIGMS NIH HHS [R01 GM060915-01, R01 GM060915] Funding Source: Medline

向作者/读者索取更多资源

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.

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