JOHN P.

COOKE

PI

Thanks for visiting our website!  I am Professor of Medicine and Director of the NHLBI funded Program in Vascular Biology and Medicine at Stanford.  We have a translational research program from molecule to man in endothelial biology.  Our strategy is to rapidly transfer our basic research insights into clinical trials using a vertically integrated approach with an array of biochemical and molecular tools, cellular and animal models, and clinical research techniques.   This translational approach is brought to bear to study the role of two different pathways on vascular structure and reactivity.  

Endothelium derived nitric oxide synthase (NOS) plays a critical role in vascular reactivity and structure.  We have shown that endothelium derived nitric oxide (NO) has anti-atherogenic properties.  Our basic research insights into the vasoprotective effects of NO have been confirmed by us and others in humans, and has led to a new therapeutic approach to cardiovascular disease (see my book "The Cardiovascular Cure:  Your self defense against Heart Attack and Stroke").   We are now studying an endogenous competitive inhibitor of the NO synthase pathway called ADMA (asymmetric dimethylarginine).  We have shown that this molecule is elevated in disorders associated with endothelial dysfunction, and plays a significant role in causing vascular disease.  We have also determined the mechanism by which ADMA becomes elevated in people with hypercholesterolemia, diabetes, and other vascular disorders.  Specifically, we find that oxidative stress impairs the activity of the enzyme (DDAH) that degrades ADMA.   ADMA accumulates and blocks NO synthesis.   Most recently, we have shown that overexpression of DDAH (in our transgenic mouse or in endothelial cell culture) can reduce ADMA levels and increase NO synthesis, with significant consequences on vascular resistance and cardiovascular physiology. We are also interested in the role of endothelium-derived NO in angiogenesis, and have documented the critical role of NO in this process.    We have shown that ADMA (by blocking NO synthesis) inhibits angiogenesis.  In our DDAH transgenic mouse, angiogenesis is enhanced (not yet published!).

Our interest in angiogenesis has led to our discovery of a novel pathway of angiogenesis.  We have discovered that nicotinic acetylcholine receptors on endothelial cells are upregulated with hypoxia, and when stimulated (by the endogenous transmitter acetylcholine), these receptors mediate endothelial tube formation in vitro, and angiogenesis in vivo.  Of great interest, this pathway is hijacked by nicotine.  By doing so, nicotine can pathologically activate tumor angiogenesis and tumor growth.  Nicotine can also stimulate the neovascularization of atherosclerotic plaque, leading to its further growth.  Our findings have led to a new paradigm for tobacco-related diseases, by which nicotine stimulates pathological angiogenesis.  These findings have also established a new platform for therapies for tobacco-related diseases, as well as therapeutic manipulations of the pathway to treat other diseases. 

If you are interested to learn more about our work and ideas, please read my book or the references below.  Also, please feel free to contact myself or Dr. Ed Chang with questions about the research.

Thanks for your interest!
John Cooke

EDWIN

CHANG

Basic Research

Edwin Chang, PhD is a combination laboratory scientist and laboratory manager for Dr. Cooke’s basic research unit. He has been a member of the team as well as an employee at Stanford since September, 2002. 

He obtained his PhD, in 1992 at McGill University, (Montreal, Canada) in which he characterized various vascular factors that are over expressed in hypertensive animals as well as in essential hypertensive humans.  Upon completion of his doctorate, Dr. Chang wished to study the biology of aging but he wished to include an interdisciplinary bent:  he intended to study the contribution of cellular and tissue aging to age-related diseases such as vascular dysfunction, atherosclerosis, skin-related disorders, arthritis, cancer etc.  To expand his research horizons, he spent the 1990’s initially as a post-doctoral fellow with Dr. Calvin Harley (a recognized pioneer in the field of aging, telomere and telomerase biology) at McMaster University (Hamilton, Ontario) and as a recruited staff scientist at Geron Corporation (Menlo Park, CA).  At both locations, he contributed to a number of fundamental studies on telomere and telomerase biology in its applicability to the age-dependent functions (or dysfunctions) of main trunk vascular endothelial cells. Evidence that ectopic telomerase expression could lengthen replicative lifespan and also improve endothelial cell survivability spurred the candidate's interest in examining the effect of telomerase action on vascular signal transduction.  His findings have been published in JBC, PNAS, Science, Nature Genetics, Biotechnology International and Experimental Cell Research.

Currently, he is attempting to uncover the mechanisms whereby activation of nicotinic/cholinergic receptor activity can drive angiogenesis and to relate these findings to pathological angiogenesis, such that occur in tumor and atherosclerotic plaque formation and to therapeutic angiogenesis which occur in dermal wound healing.  His approach is to examine nicotinic/cholinergic effect at the level of signal transduction (via MAPKII, Ca-CaM kinase, PKC and pAkt pathways) and at the level of the transcriptome (via cDNA microarray analysis).  Another approach is to link such findings to recent observations that nicotine administration can recruit and expand bone-marrow derived hematopoeitic stem cell and putative endothelial precursor cell pools in vivo in murine animal models.   Nicotine also induces NO formation in the plasma of said mice and he would like to determine the signal transduction implications of cholinergic activity of these results as well.

His personal interests include reading, study of the cinema, recreational running and hiking and overseeing the happiness and well being of his wife and his daughter. 

KATSUYA

 IIJIMA

Basic Research

I have trained in cardiovascular medicine and interventional cardiology at Cardiovascular Institute in Japan after residency in internal medicine in 1990. In particular, I have done coronary catheter intervention for ischemic heart diseases mainly for a long time. Regarding basic research, I have investigated the effects of polyphenols, one of anti-oxidants, on vascular smooth muscle cell function in cell-cycle regulation and intracellular signaling in parallel with my clinical works. I received PhD by the achievements in 2000.

I have been a postdoctoral fellow in cardiovascular medicine at Stanford University from Dec. in 2002. The hypothesis that infection with human cytomegalovirus (CMV) has been implicated in the acceleration of atherogenesis, including coronary restenosis and heart transplant vascular sclerosis, is supported by several observations. However, so far there is no evidence how CMV infection affect vascular endothelial function.   Therefore I am focusing on the role of CMV and endothelial Nitric Oxide Synthase function. In particular, I am investigating the effect of CMV infection on induction of oxidative stress, especially assessed by FACS technique, in vascular endothelial cells.

In sports, I am deeply in love with ‘GOLF’ now. Does anyone play with me?

KATHI

KARI

Clinical Research

I’m Kathi Kari, the Clinical Research Coordinator for the NO PAIN Study. (I answer to either name due to the confusion of appearing to have two 1^st names). I’ve been working at Stanford for five years in Cardiology in a variety of studies that include heart transplant, preventative medication studies and the NO PAIN alternative treatment vascular study. We have a wonderful team of brilliant researchers working to improve the quality of life. I’m very happy to be a part of this.  

My personal interests and education to date encompass a love for people, art, animals, reading, photography and travel. I studied for the ministry for two years. Other education includes clinical trials.

KEN M.

KENGATHARAN

Basic Research

Dr Kengatharan obtained his PhD in Pharmacology at the William Harvey Research Institute (of the University of London) under the mentorship of Sir John Vane (Nobel laureate and eminent British pharmacologist) and Professor Christoph Thiemermann. After completing his PhD, he held a post-doctoral position with Professor Erik Änggård (a Director of the William Harvey Research Institute), and was subsequently given the responsibility to supervise a small research group in the section of vascular biology, where he also had extensive mentoring responsibilities. The translational research that he directed involved the development of animal models of cardiovascular disease for studies that included the elucidation of the pathophysiology of vascular alterations in sepsis, diabetes and atherosclerosis. Prior to joining Stanford, he was the Vice President of Pre-clinical R&D for a South San Francisco based pharmaceutical company. Dr Kengatharan has a bachelor of science degree in pharmacology from the University of Leeds (UK) where he was the recipient of the Pfizer prize as well as the ICI Pharmacology and Therapeutics Prize.

HAKUOH

KONISHI

Basic Research

Dr. Hakuoh Konishi received his M.D. from the Juntendo University School of Medicine in 1994.  He trained in Cardiovascular Medicine at Toranomon Hospital and at Juntendo University Hospital ( Tokyo , Japan ).  He obtained his PhD in 2002 at Juntendo University .  For his doctoral thesis, he characterized the manner by which collagen-activated platelets, through an immunoreceptor, tyrosine-based activation motif play a pivotal role in the initiation and generation of neointimal hyperplasia after vascular injury.

Since July, 2003, he has been a postdoctoral research fellow at Stanford University .  His current research interest involves angiogenesis, especially the angiogenic effects of chronic treatment by nicotine.  This work is a continuation of initial reports from the Cooke laboratory (Nat. Med. 2001, Heeschen C. et al.) that described the angiogenic effects of short-term nicotine treatment.   His work at Stanford University is supported by the Uehara Memorial Foundation. 

SCOTT A.

REIFF

Administration

I have worked with the division since January 2000. I specialize in computers and I'm the divisions Expert Partner. I am a wiz in finding information via the web and also teaching others how to use their computer more efficiently and to use the web as a primary resource.

A little about me: I was born in Ohio and moved to eastern Oregon when I was 10. I attended a community college where I received an AS in Criminal Justice. I also am working on finishing my BS at a university in western Oregon. Past jobs include computer technician, desktop publisher, retail/customer service, photo finishing, and law enforcement. I worked with a sheriffs office as an Explorer, a Fish and Wildlife volunteer for the State Police, and a local city police department Reserve Police Officer all in Oregon.

My real passion is photography and travel. I have studied photography at Stanford and University of California, Santa Cruz. I recently spent 4 days in Death Valley on a photo field class. I've been making photographs for more than 10 years and have traveled to many places capturing great moments in time. I enjoy train spotting and model railroading. I am also an amateur radio operator, KB7JWM.

KARSTEN

SYDOW

Basic Research

Dr. med. Karsten Sydow has worked in the basic research lab and in the clinical research group since January 2003. His work at Stanford is supported by a two-year grant from the Deutsche Forschungsgemeinschaft (DFG) of Germany.

Dr. Sydow´s interest in endothelial function, nitric oxide and ADMA started back in 1997, when he was preparing his doctoral thesis in Prof. R.H. Bögers Lab during Medical School in Hannover, Germany. After finishing Medical School in 2000, Dr. Sydow started his Internship/Residency at Hamburg University, Department of Cardiology (Clinical supervisor: Prof. T. Meinertz). During this time, he was working in Prof. T. Münzel´s Lab continuing his interest in the endothelial function and ADMA field and getting new insights in nitrate tolerance and the role of oxidative stress in cardiovascular disease.

Since the key enzyme in the ADMA metabolism – the dimethylarginine dimethylaminohydrolase (DDAH) – is regulated in a redox-sensitive fashion, Dr. Sydow is investigating the effect of ADMA in nitrate tolerance, insulin resistance and hyperhomocyst(e)inemia using our DDAH transgenic mice at Stanford.

Karsten is probably the biggest fan of his favorite soccer team ‘96’ in California. Therefore, he gets up every Saturday morning at 6:15 am to listen to the German soccer league via the internet – even after a long night in the city.

BING YIN

WANG

Basic Research

For my MD, I trained in Medicine and Cardiovascular Medicine at Zhejiang University China. My Ph.D I was trained in Cardiovascular Medicine at Beijing University China. My Postdoctoral training in Cardiovascular Medicine at Stanford University. Research interests: atherosclerosis and angiogenesis, vascular biology, specifically the role of NO synthase.

In 1990, Dr. Cooke was recruited to Stanford University to spearhead the program in Vascular Biology and Medicine. In that year, Dr. Cooke was one of two individuals selected by the National Institutes of Health to develop national centers of excellence in Vascular Medicine. Dr. Cooke is Director of the Vascular Biology and Medicine Program at Stanford and  the Clinical Research Group in Vascular Medicine. This is a well-funded research group with grants from the National Institutes of Health, the American Heart Association, and industry. Dr. Cooke has published over 250 articles on topics of vascular medicine and biology as well as a textbook in vascular medicine. His research focuses on endothelial biology, specifically the role of NO synthase in angiogenesis and atherosclerosis.  

In addition to conducting a successful program of bench to bedside research in vascular biology and medicine, Dr. Cooke is a sought-after consultant to government and industry and has served on numerous national and international committees that deal with cardiovascular diseases, including those of the American Heart Association, American College of Cardiology and the National Heart, Lung and Blood Institute. He provides guidance to biotechnology, device and pharmaceutical firms regarding their basic and clinical research directions in vascular biology and medicine. Dr. Cooke has special expertise in development of agents for peripheral arterial disease, and is a member of the Vascular Trialists, a group of clinician-investigators with particular interest in formulating and executing trials for testing novel therapies for PAD.

Some of our work on NO

1.            Dayoub H et al: DDAH Regulates NO Synthesis: Genetic and physiological evidence. Circulation 2003; 108: 1043-1048

2.            Stuhlinger M et al:  Endothelial dysfunction induced by hyperhomocysteinemia:  Role of ADMA  Circulation 2003 Aug 26;108(8):933-8.

Some of our work on Nicotine and angiogenesis

1.            Heeschen C et al: A novel angiogenic pathway mediated by non-neuronal nicotinic acetylcholine receptors. J Clin Invest 2002 Aug;110(4):527-36

2.            Heeschen C et al: Nicotine is an agent of angiogenesis. Nicotine stimulates angiogenesis and promotes tumor growth and atherosclerosis. Nat Med 2001 Jul; 7(7):833-9

3.           Zhu et al: Second Hand Smoke Stimulates Tumor Angiogenesis and Growth, Cancer Cell 2003; 4(3):191-6