HIF-prolyl hydroxylases and cardiovascular diseases

Sucharita Sen Banerjee, Mahesh Thirunavukkarasu, Muhammad Tipu Rishi, Juan Sanchez, Nilanjana Maulik, Gautam Maulik

Research output: Contribution to journalReview article

Abstract

Prolyl hydroxylases belong to the family of iron- and 2-oxoglutamate- dependent dioxygenase enzyme. Several distinct prolyl hydroxylases have been identified. The hypoxia-inducible factor (HIF) prolyl hydroxylase termed prolyl hydroxylase domain (PHD) enzymes play an important role in oxygen regulation in the physiological network. There are three isoforms that have been identified: PHD1, PHD2 and PHD3. Deletion of PHD enzymes result in stabilization of HIFs and offers potential treatment options for many ischemic disorders such as peripheral arterial occlusive disease, myocardial infarction, and stroke. All three isoforms are oxygen sensors that regulate the stability of HIFs. The degradation of HIF-1α is regulated by hydroxylation of the 402/504 proline residue by PHDs. Under hypoxic conditions, lack of oxygen causes hydroxylation to cease HIF-1α stabilization and subsequent translocation to the nucleus where it heterodimerizes with the constitutively expressed β subunit. Binding of the HIF-heterodimer to specific DNA sequences, named hypoxia-responsive elements, triggers the transactivation of target genes. PHD regulation of HIF-1α-mediated cardioprotection has resulted in considerable interest in these molecules as potential therapeutic targets in cardiovascular and ischemic diseases. In recent years, attention has been directed towards identifying small molecule inhibitors of PHD. It is postulated that such inhibition might lead to a clinically useful strategy for protecting the myocardium against ischemia and reperfusion injury. Recently, it has been reported that the orally absorbed PHD inhibitor GSK360A can modulate HIF-1α signaling and protect the failing heart following myocardial infarction. Furthermore, PHD1 deletion has been found to have beneficial effects through an increase in tolerance to hypoxia of skeletal muscle by reprogramming basal metabolism. In the mouse liver, such deletion has resulted in protection against ischemia and reperfusion. As a result of these preliminary findings, PHDs is attracting increasing interest as potential therapeutic targets in a wide range of diseases.

Original languageEnglish (US)
Pages (from-to)347-358
Number of pages12
JournalToxicology Mechanisms and Methods
Volume22
Issue number5
DOIs
StatePublished - Jun 2012
Externally publishedYes

Fingerprint

Prolyl Hydroxylases
Hypoxia-Inducible Factor 1
Cardiovascular Diseases
Prolyl-Hydroxylase Inhibitors
Hydroxylation
Oxygen
Protein Isoforms
Enzymes
Myocardial Infarction
Stabilization
Dioxygenases
Basal Metabolism
Arterial Occlusive Diseases
Peripheral Arterial Disease
Oxygen sensors
Molecules
Reperfusion Injury
Proline
DNA sequences
Transcriptional Activation

Keywords

  • Cardioprotection
  • HIFs
  • PHD1
  • PHD2
  • PHD3
  • Reactive oxygen species

ASJC Scopus subject areas

  • Toxicology
  • Health, Toxicology and Mutagenesis

Cite this

Sen Banerjee, S., Thirunavukkarasu, M., Rishi, M. T., Sanchez, J., Maulik, N., & Maulik, G. (2012). HIF-prolyl hydroxylases and cardiovascular diseases. Toxicology Mechanisms and Methods, 22(5), 347-358. https://doi.org/10.3109/15376516.2012.673088

HIF-prolyl hydroxylases and cardiovascular diseases. / Sen Banerjee, Sucharita; Thirunavukkarasu, Mahesh; Rishi, Muhammad Tipu; Sanchez, Juan; Maulik, Nilanjana; Maulik, Gautam.

In: Toxicology Mechanisms and Methods, Vol. 22, No. 5, 06.2012, p. 347-358.

Research output: Contribution to journalReview article

Sen Banerjee, S, Thirunavukkarasu, M, Rishi, MT, Sanchez, J, Maulik, N & Maulik, G 2012, 'HIF-prolyl hydroxylases and cardiovascular diseases', Toxicology Mechanisms and Methods, vol. 22, no. 5, pp. 347-358. https://doi.org/10.3109/15376516.2012.673088
Sen Banerjee S, Thirunavukkarasu M, Rishi MT, Sanchez J, Maulik N, Maulik G. HIF-prolyl hydroxylases and cardiovascular diseases. Toxicology Mechanisms and Methods. 2012 Jun;22(5):347-358. https://doi.org/10.3109/15376516.2012.673088
Sen Banerjee, Sucharita ; Thirunavukkarasu, Mahesh ; Rishi, Muhammad Tipu ; Sanchez, Juan ; Maulik, Nilanjana ; Maulik, Gautam. / HIF-prolyl hydroxylases and cardiovascular diseases. In: Toxicology Mechanisms and Methods. 2012 ; Vol. 22, No. 5. pp. 347-358.
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