Molecular mechanisms of action and therapeutic uses of pharmacological inhibitors of hif-prolyl 4-hydroxylases for treatment of ischemic diseases

Vaithinathan Selvaraju, Narasimham L. Parinandi, Ram Sudheer Adluri, Joshua W. Goldman, Naveed Hussain, Juan Sanchez, Nilanjana Maulik

Research output: Contribution to journalReview article

Abstract

Significance: In this review, we have discussed the efficacy and effect of small molecules that act as prolyl hydroxylase domain inhibitors (PHDIs). The use of these compounds causes upregulation of the pro-angiogenic factors and hypoxia inducible factor-1α and -2α (HIF-1α and HIF-2α) to enhance angiogenic, glycolytic, erythropoietic, and anti-apoptotic pathways in the treatment of various ischemic diseases responsible for significant morbidity and mortality in humans. Recent Advances: Sprouting of new blood vessels from the existing vasculature and surgical intervention, such as coronary bypass and stent insertion, have been shown to be effective in attenuating ischemia. However, the initial reentry of oxygen leads to the formation of reactive oxygen species that cause oxidative stress and result in ischemia/reperfusion (IR) injury. This apparent "oxygen paradox" must be resolved to combat IR injury. During hypoxia, decreased activity of PHDs initiates the accumulation and activation of HIF-1α, wherein the modulation of both PHD and HIF-1α appears as promising therapeutic targets for the pharmacological treatment of ischemic diseases. Critical Issues: Research on PHDs and HIFs has shown that these molecules can serve as therapeutic targets for ischemic diseases by modulating glycolysis, erythropoiesis, apoptosis, and angiogenesis. Efforts are underway to identify and synthesize safer small-molecule inhibitors of PHDs that can be administered in vivo as therapy against ischemic diseases. Future Directions: This review presents a comprehensive and current account of the existing small-molecule PHDIs and their use in the treatment of ischemic diseases with a focus on the molecular mechanisms of therapeutic action in animal models.

Original languageEnglish (US)
Pages (from-to)2631-2665
Number of pages35
JournalAntioxidants and Redox Signaling
Volume20
Issue number16
DOIs
StatePublished - Jun 1 2014
Externally publishedYes

Fingerprint

Prolyl Hydroxylases
Therapeutic Uses
Pharmacology
Prolyl-Hydroxylase Inhibitors
Molecules
Reperfusion Injury
Oxygen
Hypoxia-Inducible Factor 1
Stents
Oxidative stress
Angiogenesis Inducing Agents
Erythropoiesis
Reentry
Blood vessels
Glycolysis
Therapeutics
Blood Vessels
Reactive Oxygen Species
Animals
Oxidative Stress

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology
  • Physiology
  • Clinical Biochemistry
  • Medicine(all)

Cite this

Molecular mechanisms of action and therapeutic uses of pharmacological inhibitors of hif-prolyl 4-hydroxylases for treatment of ischemic diseases. / Selvaraju, Vaithinathan; Parinandi, Narasimham L.; Adluri, Ram Sudheer; Goldman, Joshua W.; Hussain, Naveed; Sanchez, Juan; Maulik, Nilanjana.

In: Antioxidants and Redox Signaling, Vol. 20, No. 16, 01.06.2014, p. 2631-2665.

Research output: Contribution to journalReview article

Selvaraju, Vaithinathan ; Parinandi, Narasimham L. ; Adluri, Ram Sudheer ; Goldman, Joshua W. ; Hussain, Naveed ; Sanchez, Juan ; Maulik, Nilanjana. / Molecular mechanisms of action and therapeutic uses of pharmacological inhibitors of hif-prolyl 4-hydroxylases for treatment of ischemic diseases. In: Antioxidants and Redox Signaling. 2014 ; Vol. 20, No. 16. pp. 2631-2665.
@article{c7de7582077b4ee1a4136fb7295b2b59,
title = "Molecular mechanisms of action and therapeutic uses of pharmacological inhibitors of hif-prolyl 4-hydroxylases for treatment of ischemic diseases",
abstract = "Significance: In this review, we have discussed the efficacy and effect of small molecules that act as prolyl hydroxylase domain inhibitors (PHDIs). The use of these compounds causes upregulation of the pro-angiogenic factors and hypoxia inducible factor-1α and -2α (HIF-1α and HIF-2α) to enhance angiogenic, glycolytic, erythropoietic, and anti-apoptotic pathways in the treatment of various ischemic diseases responsible for significant morbidity and mortality in humans. Recent Advances: Sprouting of new blood vessels from the existing vasculature and surgical intervention, such as coronary bypass and stent insertion, have been shown to be effective in attenuating ischemia. However, the initial reentry of oxygen leads to the formation of reactive oxygen species that cause oxidative stress and result in ischemia/reperfusion (IR) injury. This apparent {"}oxygen paradox{"} must be resolved to combat IR injury. During hypoxia, decreased activity of PHDs initiates the accumulation and activation of HIF-1α, wherein the modulation of both PHD and HIF-1α appears as promising therapeutic targets for the pharmacological treatment of ischemic diseases. Critical Issues: Research on PHDs and HIFs has shown that these molecules can serve as therapeutic targets for ischemic diseases by modulating glycolysis, erythropoiesis, apoptosis, and angiogenesis. Efforts are underway to identify and synthesize safer small-molecule inhibitors of PHDs that can be administered in vivo as therapy against ischemic diseases. Future Directions: This review presents a comprehensive and current account of the existing small-molecule PHDIs and their use in the treatment of ischemic diseases with a focus on the molecular mechanisms of therapeutic action in animal models.",
author = "Vaithinathan Selvaraju and Parinandi, {Narasimham L.} and Adluri, {Ram Sudheer} and Goldman, {Joshua W.} and Naveed Hussain and Juan Sanchez and Nilanjana Maulik",
year = "2014",
month = "6",
day = "1",
doi = "10.1089/ars.2013.5186",
language = "English (US)",
volume = "20",
pages = "2631--2665",
journal = "Antioxidants and Redox Signaling",
issn = "1523-0864",
publisher = "Mary Ann Liebert Inc.",
number = "16",

}

TY - JOUR

T1 - Molecular mechanisms of action and therapeutic uses of pharmacological inhibitors of hif-prolyl 4-hydroxylases for treatment of ischemic diseases

AU - Selvaraju, Vaithinathan

AU - Parinandi, Narasimham L.

AU - Adluri, Ram Sudheer

AU - Goldman, Joshua W.

AU - Hussain, Naveed

AU - Sanchez, Juan

AU - Maulik, Nilanjana

PY - 2014/6/1

Y1 - 2014/6/1

N2 - Significance: In this review, we have discussed the efficacy and effect of small molecules that act as prolyl hydroxylase domain inhibitors (PHDIs). The use of these compounds causes upregulation of the pro-angiogenic factors and hypoxia inducible factor-1α and -2α (HIF-1α and HIF-2α) to enhance angiogenic, glycolytic, erythropoietic, and anti-apoptotic pathways in the treatment of various ischemic diseases responsible for significant morbidity and mortality in humans. Recent Advances: Sprouting of new blood vessels from the existing vasculature and surgical intervention, such as coronary bypass and stent insertion, have been shown to be effective in attenuating ischemia. However, the initial reentry of oxygen leads to the formation of reactive oxygen species that cause oxidative stress and result in ischemia/reperfusion (IR) injury. This apparent "oxygen paradox" must be resolved to combat IR injury. During hypoxia, decreased activity of PHDs initiates the accumulation and activation of HIF-1α, wherein the modulation of both PHD and HIF-1α appears as promising therapeutic targets for the pharmacological treatment of ischemic diseases. Critical Issues: Research on PHDs and HIFs has shown that these molecules can serve as therapeutic targets for ischemic diseases by modulating glycolysis, erythropoiesis, apoptosis, and angiogenesis. Efforts are underway to identify and synthesize safer small-molecule inhibitors of PHDs that can be administered in vivo as therapy against ischemic diseases. Future Directions: This review presents a comprehensive and current account of the existing small-molecule PHDIs and their use in the treatment of ischemic diseases with a focus on the molecular mechanisms of therapeutic action in animal models.

AB - Significance: In this review, we have discussed the efficacy and effect of small molecules that act as prolyl hydroxylase domain inhibitors (PHDIs). The use of these compounds causes upregulation of the pro-angiogenic factors and hypoxia inducible factor-1α and -2α (HIF-1α and HIF-2α) to enhance angiogenic, glycolytic, erythropoietic, and anti-apoptotic pathways in the treatment of various ischemic diseases responsible for significant morbidity and mortality in humans. Recent Advances: Sprouting of new blood vessels from the existing vasculature and surgical intervention, such as coronary bypass and stent insertion, have been shown to be effective in attenuating ischemia. However, the initial reentry of oxygen leads to the formation of reactive oxygen species that cause oxidative stress and result in ischemia/reperfusion (IR) injury. This apparent "oxygen paradox" must be resolved to combat IR injury. During hypoxia, decreased activity of PHDs initiates the accumulation and activation of HIF-1α, wherein the modulation of both PHD and HIF-1α appears as promising therapeutic targets for the pharmacological treatment of ischemic diseases. Critical Issues: Research on PHDs and HIFs has shown that these molecules can serve as therapeutic targets for ischemic diseases by modulating glycolysis, erythropoiesis, apoptosis, and angiogenesis. Efforts are underway to identify and synthesize safer small-molecule inhibitors of PHDs that can be administered in vivo as therapy against ischemic diseases. Future Directions: This review presents a comprehensive and current account of the existing small-molecule PHDIs and their use in the treatment of ischemic diseases with a focus on the molecular mechanisms of therapeutic action in animal models.

UR - http://www.scopus.com/inward/record.url?scp=84900443348&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84900443348&partnerID=8YFLogxK

U2 - 10.1089/ars.2013.5186

DO - 10.1089/ars.2013.5186

M3 - Review article

C2 - 23992027

AN - SCOPUS:84900443348

VL - 20

SP - 2631

EP - 2665

JO - Antioxidants and Redox Signaling

JF - Antioxidants and Redox Signaling

SN - 1523-0864

IS - 16

ER -