DEPARTMENT OF CARDIOVASCULAR MEDICINE KYUSHU UNIVERSITY GRADUATE SCHOOL OF MEDICAL SCIENCES

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Research Units

Molecular Cardiology Unit

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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

1. Research on the molecular mechanisms of vascular actions of angiotensin II and regulatory mechanisms of angiotensin II receptor expression




(1) Regulatory mechanisms of angiotensin II type 1 receptor expression

There are two isoforms of angiotensin II receptor, type 1 (AT1) and type 2 (AT2). Both types belong to the seven membrane-spanning receptor superfamily. AT1 is widely expressed in the cardiovascular system of the body, while AT2 is expressed mainly during the fetal stage. Currently, our group is engaged in studies on the regulation of AT1 expression. Interestingly, we found that various physiologically active substances (nitric oxide and retinoic acid) and drugs (such as statin) known to suppress atherosclerosis inhibit the expression of AT1. Although various transcription factors are involved in the regulation of AT1 expression, we are focusing on the regulation of AT1 expression by the transcription factor called SP-1.

Relevant publications
  1. Miyazaki R, Ichiki T, Hashimoto T, Inanaga K, Imayama I, Sadoshima J, Sunagawa K. SIRT1, a Longevity Gene, Downregulates Angiotensin II Type 1 Receptor Expression in Vascular Smooth Muscle Cells. Arterioscler Thromb Vasc Biol. 2008;28:1263-1269.
  2. Imayama I, Ichiki T, Patton D, Inanaga K, Miyazaki R, Ohtsubo H, Tian Q, Yano K, Sunagawa K. Liver X Receptor Activator Downregulates Angiotensin II Type 1 Receptor Expression through Dephosphorylation of Sp1. Hypertension 2008; 51: 1631-1636.
  3. Imayama I, Ichiki T, Inanaga K, Ohtsubo H, Fukuyama K, Ono H, Hashiguchi Y, Sunagawa K. Telmisartan downregulates angiotensin II type 1 receptor through activation of peroxisome proliferator-activated receptor gamma. Cardiovasc Res. 2006 ;72:184-90
  4. Fukuyama K, Ichiki T, Takeda K, Tokunou T, Iino N, Masuda S, Ishibashi M, Egashira K, Shimokawa H, Hirano K, Kanaide H, Takeshita A. Downregulation of Vascular Angiotensin II Type 1 Receptor by Thyroid Hormone. Hypertension. 2003 41:598-603.
  5. Ichiki T, Takeda T, Tokunou T, Iino N, Egashira K, Shimokawa H, Hirano K, Kanaide H, Takeshita A. Downregulation of Angiotensin II Type 1 Receptor by Hydrophobic HMG CoA Reductase Inhibitors in Vascular Smooth Muscle Cells. Arterioscler Thromb Vasc Biol. 2001;21:1896-1901.
  6. Ichiki T, Takeda K, Tokunou T, Funakoshi Y, Ito K, Iino N, Takeshita A. Reactive oxygen species-mediated homologous downregulation of angiotensin II type 1 receptor mRNA by angiotensin II. Hypertension. 2001 ;37(2 Part 2):535-540.
  7. Takeda K, Ichiki T, Tokunou T, Funakoshi Y, Iino N, Hirano K, Kanaide H, Takeshita A. Peroxisome proliferator-activated receptor gamma activators downregulate angiotensin II type 1 receptor in vascular smooth muscle cells. Circulation. 2000 ;102:1834-1839.
  8. Katoh M, Egashira K, Usui M, Ichiki T, Tomita H, Shimokawa H, Rakugi H, Takeshita A. Cardiac angiotensin II receptors are upregulated by long-term inhibition of nitric oxide synthesis in rats. Circ Res. 1998 ;83:743-751.
  9. Ichiki T, Usui M, Kato M, Funakoshi Y, Ito K, Egashira K, Takeshita A. Downregulation of angiotensin II type 1 receptor gene transcription by nitric oxide. Hypertension. 1998;31:342-348.

(2) Mechanism of signal transduction of angiotensin II: The role of cAMP response element binding protein (CREB) in blood vessels

Many recent studies have shown that angiotensin II promotes atherosclerosis. We reported that angiotensin II induces the expression of interleukin-6 and monocyte chemoattractant protein-1 in vascular smooth muscle cells to promote inflammation and infiltration of monocytes in blood vessels. From the results of our analysis of the interleukin-6 gene promotor, we have also reported that the activation of a nuclear transcription factor called CREB by angiotensin II is important in the induction of interleukin-6. 
Our studies so far on the activation of CREB in vascular smooth muscle cells have yielded the following findings:

  1. Simulation of the seven membrane-spanning receptors including angiotensin II, thrombin and PGF2α activates CREB via ERK and p38MAPK 
  2. Tumor necrosis factor α activates CREB via p38MAPK.

Research on the expression, signaling pathway and transcription factors of angiotensin II receptor

When we investigated the functions of CREB in smooth muscle cells using adenovirus expressing dominant-negative CREB, we found that CREB is involved in the following functions of vascular smooth muscle cells:

  1. Hypertrophy and proliferation (see figure on the right)
  2. Inhibition of apoptosis
  3. Migration
  4. Expression of adhesion molecule

Furthermore we have reported that the functions of CREB in blood vessels are inhibited by thyroid hormone. We have also reported that inducible cAMP early repressor (ICER), an inhibitory type transcription factor belonging to the CREB family, is induced in blood vessels by beraprost and reduces vascular lesions.

In the future, we plan to develop methods to control the function or expression of CREB in blood vessels and examine the feasibility of applying them to the treatment of atherosclerosis.

Relevant publications
  1. Ohtsubo H, , Ichiki T, Miyazaki R, Inanaga K, Imayama I, Hashiguchi Y, Sadoshima J, Sunagawa K. Inducible cAMP Early Repressor Inhibits Growth of Vascular Smooth Muscle Cell. Arterioscler Thromb Vasc Biol. 2007;27: 1549-1555
  2. Fukuyama K, Ichiki T, Imayama I, Ohtsubo H, Ono H, Hashiguchi Y, Takeshita A, Sunagawa K. Thyroid hormone inhibits vascular remodeling through suppression of cAMP response element binding protein activity. Arterioscler Thromb Vasc Biol. 2006 ;26:2049-55.
  3. Ono H, Ichiki T, Fukuyama K, Iino N, Masuda S, Egashira K, Takeshita A. cAMP-response Element-binding Protein Mediates TNFa−induced Migration of Vascular Smooth Muscle Cells. Arterioscler Thromb Vasc Biol 2004 24:1634-1639.
  4. Tokunou T, Shibata R, Kai H, Ichiki T, Morisaki T, Fukuyama K, Ono H, Iino N, Masuda S, Shimokawa H, Egashira K, Imaizumi T, Takeshita A.  Apoptosis induced by inhibition of camp response element binding protein in vascular smooth muscle cells. Circulation 2003;108:1246-1252
  5. Ichiki T, Tokunou T, Fukuyama K, Iino N, Masuda S, Takeshita A. cAMP response element binding protein mediates reactive oxygen species-induced c-fos expression. Hypertension. 2003 42:177-183.
  6. Funakoshi Y, Ichiki T, Takeda K, Tokunou T, Iino N, Takeshita A. Critical role of cAMP response element-binding protein (CREB) for angiotensin II-induced hypertrophy of vascular smooth muscle cells. J Biol Chem. 2002;277:18710-18717.
  7. Tokunou T, Ichiki T, Takeda T, Funakoshi Y, Iino N, Takeshita A. cAMP response element binding protein (CREB) mediates thrombin-induced proliferation of vascular smooth muscle cells. Arterioscler Thromb Vasc Biol. 2001; 21:1764-1769
  8. Funakoshi Y, Ichiki T, Ito K, Takeshita A. Induction of interleukin-6 expression by angiotensin II in rat vascular smooth muscle cells. Hypertension. 1999;34:118-125.

  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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