A Little About Us, A Lot About Us

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A Message from Dr Cooke.....

Thanks for visiting our website! I am the 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 see the references below.

Some of our work on NO.....

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

- 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......

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

- 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

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

Thanks for your interest!
John Cooke

Current Lab Members

2009 Cooke lab

09 cooke lab

Left to right: Scott Reiff, Arwen Hunter, Mamie Higgins, Ngan Huang, Yohannes Ghebremariam, John Cooke, Andrea Axtell, Rufaihah Jalil, Jieun Lee, Koy Thanaporn.

2009 Clinical Team

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Past Lab Members

June 2007

group

Left to right: Amir Rafie, Scott Reiff, Jenny Wu, Carlton Weatherby, Kim Edwards, Christoph Peter, Hiroshi Niiyama, John Cooke, Felix Fleissner, Maria Pitsiouni, Homa Tavana, Andew Wilson, Ngan Huang, Cecile Holweg.

August 2005

cooke lab

Left to right: Laura Dodera, Homa Tavana, Bryant Lin, Eiichiro Kimura, Jan Kielstein, Scott Reiff, Ken Kengatheran, Christoph Peter, Jenny Wu, John Cooke, Kendall Beck, Randall Harada, Hakuoh Konishi, Bing Wang, Cecile Holweg, Maria Pitsiouni, Regina Katzenberg.

February 2005

lab

Left to right, Eiichiro Kimura, Bing Wang, Hakouh Konishi, Homa Tavana, Sara McGee, John Cooke, Jan Kielstein, Ken Kengatheran, Randall Harada, Edwin Chang, Martin Ng, Jenny Wu, Carl Mondon. Not pictured: Scott Reiff, Regina Katzenberg, Kathi Kari

clinical team

A tight clinical team makes the study better

lab

May 2003

Left to right: Edwin Chang, Scott Reiff, Gina Droll, Karsten Sydow, Katsuya Iijima, Bing Wang, John Cooke, Ken Lin, Johannes Jacobi, Kathi Kari, Laurel Waring

November 2001