DEPARTMENT OF CARDIOVASCULAR MEDICINE KYUSHU UNIVERSITY GRADUATE SCHOOL OF MEDICAL SCIENCES

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Research Units

Molecular Cardiology Unit

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menu Research Outline Main Research Themes and Relevant Publications Principle Investigator of the group Staff and Research Focus Research Outline Main Research Themes and Relevant Publications Profile of Lead Researcher Staffs and the Research Focus 研究概要 主要なテーマと関連論文 主任研究者情報 研究室情報

Main Research Themes and Relevant Publications


  1. Research on the molecular mechanisms of vascular actions of angiotension II and regulatory mechanisms of angiotensin II receptor expression
  2. Research on the effects of senescence and apoptosis of blood vessels on the development of vascular lesions
  3. Research on the roles of hypoxic signals on inflammation and angiogenesis

3. Research on the roles of hypoxic signals on inflammation and angiogenesis



Living organisms maintain an intricate mechanism to sense the oxygen concentration of their surroundings. When oxygen concentration is lowered, living organism activate the hypoxic signals to adapt to the hypoxic state. Molecules called hypoxia inducible factor (HIF) and prolyl hydroxylase (PHD) are the key molecules of hypoxic signals. HIF is a transcription factor induced by hypoxia, and increases gradually when the oxygen concentration is lowered, inducing vascular endothelial growth factor (VEGF), erythropoietin (EPO) and other genes to stimulate angiogenesis and hematopoiesis. The HIF level is regulated by PHD (an oxygen-sensitive protein) in an oxygen concentration-dependent manner (Fig. 1). When oxygen is present in sufficient concentration, HIF is degraded by PHD through hydroxylation of a specific proline residue. On the other hand, when oxygen level is lowered, the enzymatic activity of PHD is marked lowered; as a result HIF is not degraded but migrates into the nucleus where it activates gene activation in a hypoxia response element (HRE)-dependent manner.

The hypoxic signal pathway is known to be activated under various pathological states. For example, the lipid core of arteriosclerotic lesion and the adipose tissue under obese condition are in a strongly hypoxic state with pO2 of around 10 mmHg, and activation of hypoxic signals has been reported. While the activation of hypoxic signals is a response to improve the hypoxic state, it is possible that the activated hypoxic signals in some lesions may act in a direction toward aggravating inflammation; through enhancing inflammation and apoptosis as well as further supplying inflammatory cells via induced angiogenesis. In other words, the hypoxic state together with the activation of hypoxic signals in arteriosclerotic lesions and adipose tissues may form a vicious cycle to promote progression of the lesions. Conversely, induction of more effective angiogenesis is essential in the treatment of ischemic diseases such as myocardial infarction and cerebral infarction. In this case, stronger activation of hypoxic signals is required. Therefore it may be possible to treat a wide range of diseases by positive or negative control of hypoxic signals.

Using genetic recombination mice, we are employing the Cre-loxP system to develop a method of cell-specific control of hypoxic signal activity (Fig. 2). The exon sequence flanked by the two loxP sequences is cleaved by the action of Cre recombinase, resulting in deactivation of the gene. Since the expression of Cre is controlled by the promotor of specific genes expressed in specific cells, it is possible to delete the gene only in the desirable cells. Using this technique, we are attempting to produce mice defective in PHD or HIF specifically in myocardial cells or adipose cells. Recently many attempts are being made to develop PHD inhibitor as a new therapeutic for ischemic heart diseases. We hope that the information obtained from our mouse model will be helpful in the treatment of diseases such as myocardial infarction and obesity that are showing an upward trend in recent years.

図1

When the oxygen concentration is progressively lowered, PHD activity gradually decreases. The degradation pathway mediated by hydroxylation of HIF-α (shown on the left of the figure) is inhibited, and is replaced by a shift to the reaction pathway (shown on the right). HIF-α that escapes degradation forms a dimer with HIF-β and binds with the hypoxia response element to promote the expression of VEGF, EPO and other genes.


図2

When a mouse harboring a specific exon of phd or HIF gene flanked by two loxP sequences (left) is mated with a mouse expressing Cre recombinase only in myocardial cells (right), it is possible to produce mice with PHD or HIF deficit only in myocardial cells. These mice allow the analysis of the roles of PHD and HIF in myocardial cells at in vivo level.

 


Relevant publications
  1. Fong GH, Takeda K. Role and regulation of prolyl hydroxylase domain proteins. Cell Death Differ. 15:635-41;2008
  2. Takeda K, Aguila HL, Parikh NS, Li X, Lamothe K, Duan LJ, Takeda H, Lee FS, Fong GH. Regulation of adult erythropoiesis by prolyl hydroxylase domain proteins. Blood. 111:3229-35:2008
  3. Takeda K, Cowan A, Fong GH. Essential role for prolyl hydroxylase domain protein 2 in oxygen homeostasis of the adult vascular system. Circulation. 116:774-81;2007
  4. Takeda K, Fong GH. Prolyl hydroxylase domain 2 protein suppresses hypoxia-induced endothelial cell proliferation. Hypertension. 49:178-84;2007
  5. Takeda K, Ho VC, Takeda H, Duan LJ, Nagy A, Fong GH. Placental but not heart defects are associated with elevated hypoxia-inducible factor alpha levels in mice lacking prolyl hydroxylase domain protein 2. Mol Cell Biol. 26:8336-46;2006

  1. Research on the molecular mechanisms of vascular actions of angiotension II and regulatory mechanisms of angiotensin II receptor expression
  2. Research on the effects of senescence and apoptosis of blood vessels on the development of vascular lesions
  3. Research on the roles of hypoxic signals on inflammation and angiogenesis

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