PHA/NHLBI K08/K23 Award Winner 2007

Peter Oishi, M.D.Peter Oishi, M.D.

University of California San Francisco
“Vascular Dysfunction with Increased Pulmonary Blood Flow: A Role for PPAR Gamma”
NHLBI Mentored Clinical Scientist Development Award (K08)
July 1, 2007 – June 30, 2012

Summary of Research Project:

Vascular Dysfunction with Increased Pulmonary Blood Flow: A Role for PPAR Gamma

Congenital heart defects, which are birth defects that result in anatomic abnormalities of the heart, afflict as many as 1% of all born infants. Although there are many different types of defects, several common defects disrupt the normal separation between the blood that flows from the heart to the lungs and the blood that flows from the heart to the body. As a result, these defects cause an abnormally increased amount of blood to flow through the lungs. Over time, this increased blood flow to the lungs causes injury to the blood vessels of the lung. Normally, the blood vessels of the lung are maintained in a relaxed dilated state, and thus allow blood to flow easily under low pressure. However, after exposure to abnormally increased blood flow, the blood vessels of the lung begin to loose this relaxed state, and become prone to periods of intense constriction. This can diminish the amount of oxygen delivered to the body from the lungs, and can place a significant strain on the heart which must pump blood through the lungs against an abnormally increased pressure. Even worse, if the disease process continues, the blood vessels of the lung begin to change by thickening and decreasing their internal size. This can permanently increase the resistance of blood flow through the lung and increase the pressure within the lung’s vessels. This increased pressure is called hypertension, and since it develops within the lung, it is called pulmonary hypertension.

My research is focused on understanding the basic mechanisms that link increased blood flow through the lungs with the development of this pulmonary hypertension. Only by understanding these processes, can novel treatment strategies be developed to help patients with this disease. In order to study basic biochemical, cellular, and molecular mechanisms that control the development of pulmonary hypertension, lung tissue and lung blood vessels must be examined. This presents a significant problem for researchers, since obtaining lung tissue from patients would require very invasive and potentially dangerous surgery. Therefore, our laboratory group has developed a large animal model that closely mimics the human disease. With this model the controlling mechanisms can be explored.

We have previously demonstrated alterations in important factors produced by lung vessels, such as nitric oxide and endothelin-1, that contribute to the development of pulmonary hypertension in the setting of congenital heart defects. In fact, therapies that increase nitric oxide signaling (sildenafil) and that block endothelin-1 (bosentan) are currently used to treat patients with pulmonary hypertension.

More recently, our work has explored the role of reactive oxygen species, which are molecules derived from oxygen that contribute to the development of a number of vascular diseases, including hypertension, diabetes, and stroke, in the development of pulmonary hypertension. Furthermore, preliminary studies in our laboratory have identified a potential role for a recently discovered class of receptors in the body termed peroxisome proliferator-activated receptors, or PPAR. This line of research is exciting because drugs that activate these receptors are currently available commercially for the treatment of diabetes.

Curriculum Vitae

Position: Assistant Professor
Department of Pediatrics, Division of Critical Care
University of California San Francisco

Education and Training

  • 1988-1992 Swarthmore College, Swarthmore, PA. BA, English Literature and Psychology.
  • 1992-1993 University of Pennsylvania, Philadelphia, PA. Post-Baccalaureate Pre-Medical Program.
  • 1994-1998 Albany Medical College, Albany, NY. Doctor of Medicine.
  • 1998-2001 Resident Physician, Department of Pediatrics, University of New Mexico Health Sciences Center, Albuquerque, New Mexico.
  • 2001-2004 Clinical Fellow, Division of Critical Care, Department of Pediatrics, University of California, San Francisco and Children’s Hospital and Research Center at Oakland.
  • 2001-2004 Research Fellow, Cardiovascular Research Institute, University of California, San Francisco.

 

Certification and Licensure

  • 2002 California Medical License, Certificate Number A77578.
  • 2003 American Board of Pediatrics, General Pediatrics.
  • 2004 American Board of Pediatrics, Pediatric Critical Care Medicine, Board Eligible

 

Honors and Awards

  • 1992 BA with Honors – Swarthmore College. Sigma Xi
  • 2004 NIH, Pediatric Loan Repayment Program
  • 2004 NIH K12, Pediatric Critical Care Scientist Development Program.
  • 2006 Entelligence Young Investigators Award, Actelion Ltd.
  • 2006 NIH Pediatric Loan Repayment Program – Renewal
  • 2007 NIH, K08
  • 2007 Pulmonary Hypertension Association, Mentored Clinical Scientist Development Award

 

Professional Organizations

  • 2005 Ad hoc referee, Pediatric Critical Care Medicine.

 

Memberships

  • 1998 American Academy of Pediatrics
  • 2001 Society for Critical Care Medicine
  • 2007 Pulmonary Hypertension Clinicians and Researchers
  • 2007 Western Society for Pediatric Research

 

Invited Scientific Presentations

  • 2003 Poster Presentation, “Alterations in endothelial function during inhaled nitric oxide exposure,” Shapiro Symposium, University of California, San Francisco.
  • 2004 Poster Presentation, “Acute alterations in nitric oxide and endothelin-1 following surgically-induced acute increases in pulmonary blood flow in the postnatal lamb,” Pediatric Academic Societies’ Meeting, San Francisco, CA.
  • 2004 Platform Presentation, “PEG-SOD prevents rebound pulmonary hypertension and the NOS inhibition associated with inhaled nitric oxide therapy in lambs,” Pediatric Academic Societies’ Meeting, San Francisco, CA.
  • 2004 Platform Presentation, “Endothelial signaling interactions following surgically induced acute increases in pulmonary blood flow in the lamb,” American Heart Association Scientific Sessions Meeting, New Orleans, LA.
  • 2005 Platform Presentation, “Increased Pulmonary Blood Flow is Associated with an Increase in NOS Activity and Gene Expression But a Decrease in Bioavailable NO in an Animal Model of Congenital Heart Disease – A role for superoxide production?” Pediatric Academic Societies’ Meeting, Washington, D.C.
  • 2005 Lecture, “Alterations in endogenous endothelial function in the pulmonary circulation -- The role of reactive oxygen species,” Pediatric Critical Care Scientist Development Program Annual Meeting, Park City, UT.
  • 2006 Poster Presentation, “Alterations in Downstream Mediators of the NO-cGMP Cascade in a Lamb Model of Congenital Heart Disease with Increased Pulmonary Blood Flow,” Pediatric Academic Societies’ Meeting, San Francisco, CA.
  • 2006 Pediatric Grand Rounds, “Pulmonary Vascular Dysfunction Associated With Congenital Heart Disease,” University of New Mexico Health Sciences Center.

 

Research Support


Title: Novel NO-ET-1-ROS Interactions in the Pulmonary Vasculature
Principal Investigator: Peter Oishi
Agency: National Institute of Child Health and Human Development, K12
1/01/05 to 12/31/10
Pediatric Critical Care Scientist Development Program – The objective of the project is to delineate alterations in endogenous pulmonary endothelial function that occur during exogenous augmentation of pulmonary NO-cGMP signaling.

Title: Endothelin-1-Reactive Oxygen Species Interactions in Pulmonary Hypertension
Principle Investigator: Peter Oishi
Agency: Actelion Pharmaceuticals Ltd., Entelligence Young Investigators Program
7/01/06 to 6/30/07

Title: Vascular Dysfunction with Increased Pulmonary Blood Flow: A role for PPAR Gamma
Principle Investigator: Peter Oishi
Agency: National Heart Lung and Blood Institute, K08
1/01/07 to 12/31/10
The objective of this project is to elucidate the role of PPAR gamma in the pulmonary vascular dysfunction that develops secondary to congenital cardiac defects with increased pulmonary blood flow.

Title: Vascular Dysfunction with Increased Pulmonary Blood Flow: A role for PPAR Gamma
Principle Investigator: Peter Oishi
Agency: Pulmonary Hypertension Association, K08 Supplemental Award
7/01/07 to 6/30/12

Other Published Articles


Journal articles listed below can be found through Pubmed:

  1. Oishi PE, Fineman JR, “Pharmacologic Therapy for Persistent Pulmonary Hypertension of the Newborn: As “Poly” as the Disease Itself,” Pediatr Crit Care Med; 5: 94-6, 2004.
  2. Thelitz S, Oishi P, Sanchez LS, Bekker JM, Ovadia B, Johengen MJ, Black SM, Fineman JR, “PDE-3 inhibition prevents inhaled nitric oxide-induced rebound pulmonary hypertension,” Pediatr Crit Care Med; 5: 234-39, 2004.
  3. Fitzgerald RK, Oishi P, Ovadia B, Ross GA, Reinhartz O, Johengen MJ, Fineman JR, “Tezosentan, a combined parenteral endothelin receptor antagonist, produces pulmonary vasodilation in lambs with acute and chronic pulmonary hypertension,” Pediatr Crit Care Med; 5: 571-7, 2004.
  4. Fratz S, Meyrick B, Ovadia B, Johengen M, Reinhartz O, Azakie A, Ross G, Fitzgerald R, Oishi P, Hess J, Black SM, Fineman JR, “Chronic endothelin-A receptor blockade in lambs with increased pulmonary blood flow and pressure,” Am J Physiol Lung Cell Mol Physiol; 287(3):L592-7, 2004.
  5. Ross GA*, Oishi P*, Azakie A, Fratz S, Ovadia B, Fitzgerald RK, Johengen MJ, Harmon C, Hendricks-Munoz K, Xu J, Black SM, Fineman JR, “Alterations during inhaled nitric oxide in lambs with increased pulmonary blood flow: implications for rebound pulmonary hypertension,” Am J Physiol Lung Cell Mol Physiol; 288: L27-35, 2005. *These authors contributed equally.
  6. Oishi P, Grobe AC, Benevidez EH, Ovadia B, Harmon C, Ross GA, Hendricks-Munoz K, Xu J, Black SM, Fineman JR, “Inhaled Nitric Oxide Induced NOS Inhibition and Rebound Pulmonary Hypertension: A role for superoxide and peroxynitrite in the intact lamb,” Am J Physiol Lung Cell Mol Physiol, 2006 Feb; 290(2): L359-66. Epub 2005 Oct 28.
  7. Chie-Youn Shih, Anil Sapru, Peter Oishi, Anthony Azakie, Cynthia Harmon, Ritu Asija, Ian Adatia, Jeffrey R. Fineman, “Alterations in Plasma B-type Natriuretic Peptide Levels Following Repair of Congenital Heart Defects – A Potential Perioperative Marker,” J Thorac Cardiovasc Surg. 2006 Mar; 131(3):632-8.
  8. Oishi P, Azakie A, Harmon C, Fitzgerald R, Hendricks-Munoz K, Xu J, Grobe AC, Benavidez EH, Black SM, Fineman JR, “Nitric Oxide-Endothelin-1 Interactions After Surgically Induced Acute Increases in Pulmonary Blood Flow in the Intact Lamb,” Am J Physiol Heart Circ Physiol. 2006 May; 290(5):H1922-32. Epub 2005 Dec 9.
  9. Grobe AC, Wells SM, Benavidez E, Oishi P, Azakie A, Fineman JR, Black SM, “Increased oxidative stress and pulmonary hypertension: Role of antioxidant systems, NADPH oxidase, and eNOS,” Am J Physiol Lung Cell Mol Physiol. 2006 Jun; 290(6):L1069-77.
  10. Oishi PE, Fineman JR., “BNP for pediatrics-Not quite ready for primetime,” Pediatr Crit Care Med. 2006 Jul;7(4):388-389.
  11. Chikovani O, Hsu J, Keller R, Karl TR, Azakie A, Adatia I, Oishi P, Fineman JR, “B-type natriuretic peptide (BNP) levels predict outcomes for children on extracorporeal life support (ECLS) after cardiac surgery,” J Thorac Cardiovasc Surg, In Press.
  12. Hsu J, Keller R, Chikovani O, Cheng H, Hollander SA, Karl TR, Azakie A, Adatia I, Oishi P, Fineman JR, “B-type natriuretic peptide (BNP) levels predict outcome after neonatal cardiac surgery,” J Thorac Cardiovasc Surg, In Press.

 

Book Chapters

  1. Peter Oishi, Julien I. Hoffman, Bradley P. Fuhrman, Jeffrey R. Fineman. Regional Circulation. In: Fuhrman BP, Zimmerman JJ, eds. Pediatric Critical Care. 3rd ed. Philadelphia: Mosby; 2006:225-250.
  2. Peter Oishi and Jeffrey Fineman. Diseases of the Pulmonary Vascular System. In: Wheeler D ed. Pediatric Critical Care, in Press. 
  3. Peter Oishi, David Teitel, Julien Hoffman, Jeffrey R. Fineman. Cardiovascular Physiology. In: Roger’s Textbook of Pediatric Critical Care, 4th Edition, in Press.
  4. Peter Oishi and Jeffrey R. Fineman. Pulmonary Endothelial Control of the Pulmonary Microcirculation. In: Reddington A ed., in Press.

Abstracts

  1. Schneider AM, Thomas E, Jacobs M, Oishi P, Meagher RJ, Asmann P, “The ameliorative effect of repeated injections of scopolamine hydrobromide on recovery from brain damage: an analysis of generality and mechanism,” Society for Neuroscience Abstracts, 18, 870, 1992.
  2. Sohrab Fratz, Barbara Meyrick, Boaz Ovadia, Michael Johengen, Olaf Reinhartz, Greg Ross, Robert Fitzgerald, Peter Oishi, John Hess, Stephen M Black, Jeffrey R Fineman, “Chronic Endothelin-A receptor blockade lowers pulmonary vascular resistance, augments alveolar growth, and does not alter eNOS/ET-1 signaling of lambs with increased pulmonary blood flow and pressure,” Abstract, Circulation, 108, 17: IV-359, 2003. 
  3. Oishi PE, Ovadia B, Myette M, Harmon C, Johengen M, Black SM, Fineman JR. “PEG-SOD prevents rebound pulmonary hypertension and the NOS inhibition associated with inhaled nitric oxide therapy in lambs,” Ped Research, 55, 59A, 2004. 
  4. Oishi PE, Fitzgerald R, Azakie A, Ovadia B, Ross G, Myette M, Hendricks-Munoz K, Xu J, Black SM, Fineman JR, “Acute alterations in nitric oxide and endothelin-1 following surgically induced increases in pulmonary blood flow in the postnatal lamb,” Ped Research, 55, 63A, 2004. 
  5. Peter Oishi, Anthony Azakie, Cynthia Harmon, Robert Fitzgerald, Karen Hendricks-Munoz, Jie Xu, Albert C Grobe, Eileen H Benavidez, Stephen M Black, Jeffrey R Fineman, “Endothelial signaling interactions following surgically induced acute increases in pulmonary blood flow in the lamb,” Circulation, 110, III-569, 2004.
  6. Albert C. Grobe, Eileen Benevidez, Peter Oishi, Jeffrey R. Fineman, Stephen M. Black, “The role of oxidant stress in the development of pulmonary hypertension,” Ped Research, 57, 2521A, 2005.
  7. Chie-Youn Shih, Cynthia Harmon, Peter Oishi, Ritu Asija, Anil Sapru, Anthony Azakie, Michael Myette, Stephen M. Black, Jeffrey R. Fineman, “Alterations in plasma B-type natriuretic peptide following repair of congenital heart disease with cardiopulmonary bypass – a potential prognostic tool, “ Ped Research, 57, 2323A, 2005. 
  8. Peter Oishi, Anthony Azakie, Cynthia Harmon, Albert Grobe, Eileen Benevidez, Chie-Youn Shih, Stephen M. Black, Jeffrey R. Fineman, “Increased pulmonary blood flow increases NOS activity but decreases bioavailable NO in an animal model of congenital heart disease—a role for superoxide production?” Ped Research, 57, 2321A, 2005.
  9. Sandra M. Wells, Albert C. Grobe, Peter Oishi, Jeffrey R. Fineman, Stephen M. Black, “Increased Asymmetric Dimethylarginine (ADMA) Levels in Lambs with Pulmonary Hypertension and Increased Pulmonary Blood Flow Is Due to a Hydrogen Peroxide Mediated Decrease in Dimethylarginine Dimethylaminohydrolase (DDAH) Activity,” E-PAS2006:59, 4685.3.
  10. Cynthia Harmon, Sandra M. Wells, Chie-Youn Shih, Anil Sapru, Michael Myette, Peter Oishi, Stephen M. Black, Jeffrey R. Fineman, “Asymmetric Dimethylarginine (ADMA) Levels Following Repair of Congenital Heart Disease (CHD),” E-PAS2006:59, 4835.107. 
  11. Peter Oishi, Albert Grobe, Cynthia Harmon, Anthony Azakie, Chie-Youn Shih, Stephen M. Black, Jeffrey R. Fineman, “Alterations in Downstream Mediators of the NO-cGMP Cascade in a Lamb Model of Congenital Heart Disease with Increased Pulmonary Blood Flow (PBF),” E-PAS2006:59,4835.108
  12. Jong-Hau Hsu, Roberta Keller, Omar Chikovani, Henry Cheng, Seth A. Hollander, Tom R Karl, Anthony Azakie, Ian Adatia, Peter Oishi, Jeffrey R Fineman, “Postoperative increases in B-type natriuretic peptide (BNP) predict poor outcome following neonatal cardiac surgery,” Crit Care Med, 34, 207A, 2006.
  13. Omar Chikovani, Jong-Hau Hsu, Roberta Keller, Tom R Karl, Anthony Azakie, Ian Adatia, Peter Oishi, Jeffrey R Fineman, “B-type natriuretic peptide (BNP) levels predict outcomes in children on extracorporeal life support (ECLS) after cardiac surgery,” Crit Care Med, 34, 218A, 2006.

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