Yale School of Medicine

Internal Medicine

Internal Medicine, Yale School of Medicine

Internal Medicine
333 Cedar Street
Room LMP-1072
P.O. Box 208056
New Haven, CT 06520-8056

Yasuko Iwakiri, Ph.D.

Yasuko Iwakiri, Ph.D.

Assistant Professor
Section of Digestive Diseases
Department of Internal Medicine
Yale University School of Medicine

Research Interests

These are the two major topics of the current interest in my research:

  • Nitric oxide (NO) signaling in endothelial cells
  • Mechanisms of arterial abnormality observed in portal hypertension

Nitric oxide (NO) signaling in endothelial cells
Endothelial cells produce NO by the enzyme, endothelial NO synthase (eNOS), which has unique patterns of subcellular localizations - cytosolic aspect of the Golgi apparatus and plasma membrane. Previously, we demonstrated that Golgi localization of eNOS influences local NO concentration, which creates favorable environment for the cysteine thiol modification of proteins by NO, known as S-nitrosylation, and influences endothelial cell function, such as protein trafficking (see Iwakiri et al., PNAS 2006). Thus, it was hypothesized that eNOS at the Golgi apparatus nitrosylates (modifies cysteine thiol of) the Golgi proteins and regulates Golgi proteins’ functions such as trafficking. Recently we identified those Golgi proteins that are potentially considered as the targets for S-nirosylation, using subcellular proteomics approach. This project will determine some of important Golgi proteins that may be regulated by NO in endothelial cells.

Mechanisms of arterial abnormality observed in portal hypertension
A hyperdynamic splanchnic and systemic circulation is typical of cirrhotic patients and has been observed in all experimental forms of portal hypertension. The hyperdynamic circulation is most likely initiated by arterial vasodilatation, leading to central hypovolemia, sodium retention and an increased intravascular volume. Arterial vasodilatation is regulated by a complex interplay of various vasodilator molecules and factors that influence the production of those vasodilator molecules. Nitric oxide (NO) has been recognized as the most important vasodilator molecule that mediates the excessive arterial vasodilatation observed in portal hypertension. eNOS is the primary NO producing enzyme responsible for excessive NO production and vasodilatation observed in the arterial splanchnic circulation in portal hypertension.

My research focuses on elucidating the molecular mechanisms responsible for the up-regulation of eNOS in arteries of the splanchnic circulation in cirrhosis with portal hypertension.

Selected Publications

Manuscripts

  • Fernández-Hernando, C., Ackah, E., Yu, J., Suárez, J., Murata, T., Iwakiri, Y., Prendergast, J., Miao, R. Q., Birnbaum, M. J., and Sessa, W. C. Loss of Akt1 leads to severe atherosclerosis and occlusive proximal coronary artery disease: Evidence for a dominant role of vascular Akt1 in atheroprotection. Cell Metabolism. 2007; 6(6): 446-57.
  • Iwakiri, Y. The molecules: Mechanisms of arterial vasodilatation observed in the splanchnic and systemic circulation in portal hypertension. J Clin Gastroenterol. 2007; 41(10 Suppl 3): S288-94.
  • Iwakiri, Y. and Groszmann, R.J. Vascular Endothelial Dysfunction in Cirrhosis.Journal of Hepatology. 2007; 46(5): 927-934.
  • Lee, C.H., Loureiro-Silva, M.R., Abraldes, J.G., Iwakiri, Y., Haq, O., and Groszmann, R.J.  Decreased intrahepatic response to alpha(1)-adrenergic agonists in lipopolysaccharide-treated rats is located in the sinusoidal area and depends on Kupffer cell function. J Gastroenterol Hepatol 2007; 22(6): 893-900.
  • Kwon, S., Groszmann, R.J., and Iwakiri, Y (corresponding). Increased Neuronal Nitric Oxide Synthase Interaction with Soluble Guanylate Cyclase Contributes to the Splanchnic Arterial Vasodilation in Portal Hypertensive Rats. Hepatology Research. 2007; 37(1): 58-67.
  • Iwakiri, Y., Satoh, A., Chatterjee, S., Shah, V., Chalouni, C., Toomre, D., Fulton, D., Groszmann, R.J., and Sessa. W.C. Nitric Oxide Synthase Establishes a Local Nitric Oxide Gradient Regulating S-nitrosylation and Protein Secretion. Proc Natl Acad Sci USA. 2006; 103(52): 19777-82.
  • Iwakiri, Y. and Groszmann, R.J. The Hyperdynamic Circulation of Chronic Liver Diseases: From the Patient to the Molecule.  Hepatology. 2006: S121-31.
  • Abraldes, J.G. *, Iwakiri, Y. *, Loureiro-Silva, M., Haq, O., Sessa, W.C., and Groszmann, R.J.  Mild increases in portal pressure upregulate VEGF and eNOS in the intestinal microcirculatory bed leading to the hyperdynamic state.  Am J Physiol. Liver and Gastro. 2006; 290(5):G980-7.
  • Loureiro-Silva, M.R., Iwakiri,Y., Haq, O., and Groszmann, R.J. Phosphodiesterase-5 (PDE-5) is up-regulated in cirrhotic rat livers; potential role for PDE-5 inhibitors in reducing the increased intrahepatic vascular tone in cirrhosis.  J Hepatology. 2006; 44(5): 886-93.
  • Ackah, E., Yu, J., Zoellner, S., Iwakiri, Y., Skurk, C., Shibata, R., Ouchi, N., Easton, R.M., Galasso, G., Birnbaum, M.J., Walsh, K., Sessa, W.C. Akt1/protein kinase B alpha is critical for ischemic and VEGF-mediated angiogenesis. J Clin Invest. 2005; 115(8): 2119-2127.
  • Fulton, D., Babbitt, R., Zoellner, S., Fontana, J., Acevedo, L., McCabe, T.J., Iwakiri, Y., and Sessa, W.C. Targeting of endothelial nitric oxide synthase to the cytoplasmic face of the golgi or plasma membrane regulates Akt- versus calcium-dependent mechanisms for nitric oxide release. J Biol Chem. 2004; 279(29): 30349-57.
  • Loureiro-Silva, M.R., Iwakiri, Y., Cadelina, G., Sessa, W.C., and Groszmann, R.J. A liver-specific nitric oxide donor improves the intra-hepatic vascular response to both portal blood flow increase and methoxamine in cirrhotic rats. J Hepatol. 2003; 39(6): 940-6.
  • Tsai, M-H., Iwakiri,Y., Sessa, W.C., and Groszmann, R.J. Mesenteric vasoconstriction triggers nitric oxide overproduction in the superior mesenteric artery of portal hypertensive rats. Gastroenterology. 2003;125(5):1452-61.
  • Gratton, J-P., Lin, M., Yu,J., Weiss, E.D., Jiang, Z.L., Fairchild, T.A., Iwakiri,Y., Groszmann, R.J., Claffey, K.P., Cheng, Y-C., and Sessa. W.C. Selective inhibition of tumor microvascular permeability by cavtratin blocks tumor progression in mice. Cancer Cell. 2003; 4: 31-39.
  • Iwakiri, Y., Tsai, M-H., McCabe, T.M., Gratton, J-P., Fulton, D., Groszmann, R.J., and Sessa, W.C. The phosphorylation of endothelial nitric oxide synthase initiates excessive nitric oxide production in the early phases of portal hypertension. Am J Physiol Heart and Circ. 2002; 282: H2084-H2090.
  • Iwakiri, Y., Cadelina, G., Sessa, W.C., and Groszmann, R.J. Mice with targeted gene deletion of eNOS develope the hyperdynamic circulation associated with portal hypertension. Am J Physiol. Gastro and Liver physiol. 2002;283(5):G1074-81.
  • Iwakiri, Y., Sampson, D.A., and Allen, K.G.D. Suppression of cyclooxygenase-2 and inducible nitric oxide synthase expression by conjugated linoleic acid in murine macrophages. Prostaglandins, Leukotrienes and Essential Fatty Acids. 2002; 67(6):437-445.
  • Watkins, B.A., Li, Y., Rogers, L.L., Hoffmann, W.E., Iwakiri, Y., Allen, K.G.D., and Seifert, M.F. Effect of red palm olein on bone tissue fatty acid composition and histomorphometric parameters. Nutrition Research. 2001;21:199-213.
* Sharing first authorship

Manuscripts submitted

  • Iwakiri, Y., Grisham, M., and Shah, V. Vascular Biology and Pathobiology of the Liver: Report of a Single Topic Symposium. Hepatology. 2007 (submitted).

Book Chapter

  • Iwakiri, Y. and Sessa, W.C. Role of endothelium derived nitric oxide in vascular control: The complex role of nitric oxide in liver disease. 2001. In AASLD Postgraduate Course 2001, Complications of cirrhosis: pathogenesis, consequences and therapy. pp 24-28.
  • Iwakiri, Y. and Groszmann, R.J. The Paradox: Vasoconstriction and Vasodilation. In Portal hypertension in the 21st century. Kluwer Academic Publishers. Lancaster, United Kingdom. 2004.
  • Iwakiri. Y. Prevention of the formation of varices: Molecular markers in portal hypertension. In: Portal hypertension IV – Proceedings from the 4th Baveno International consensus workshop, edited by Roberto de Franchis. Blackwell Publishing, Oxford England. 2005.

Contact

Campus Address
Digestive Diseases
Yale University School of Medicine
333 Cedar Street (LMP 1080)
New Haven, CT 06520

E-mail
yasuko.iwakiri@yale.edu

Office Phone
(203) 785-6204

Lab
(203) 785-4313