John Cooke, MD, PhD

Research/Lab website:   My Lab Site

I am Professor of Medicine and Associate Director (Education and Training)of the Stanford Cardiovascular Institute. My research group performs translational work in endothelial biology from molecule to man. The goal is to transfer 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 on two different pathways for 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. There is an endogenous competitive inhibitor of the NO synthase pathway called ADMA (asymmetric dimethylarginine). We find that this molecule is elevated in disorders associated with endothelial dysfunction, and plays a significant role in causing vascular disease. ADMA becomes elevated in people with hypercholesterolemia, diabetes, and other vascular disorders. We find that oxidative stress impairs the activity of the enzyme (DDAH) that degrades ADMA. ADMA accumulates and blocks NO synthesis. 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 interested in the role of ADMA to inhibit angiogenesis. In our DDAH transgenic mouse, ADMA is reduced and angiogenesis is enhanced (Jacobi et al Circulation 2005).
More recently we have serendipitously discovered a new pathway modulating angiogenesis. 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. Thus nicotine can pathologically activate tumor angiogenesis and tumor growth. Nicotine can also stimulate the neovascularization of atherosclerotic plaque, leading to its further growth. These findings suggest a new paradigm for tobacco-related diseases, and provide for a new platform for therapeutic manipulations of the pathway.
If you are interested to learn more about our work and ideas, please read the references below and/or contact me. Thanks for your interest!John Cooke**

A nationally recognized figure in endothelial biology, Dr. Cooke trained in Cardiovascular Medicine at the Mayo Clinic and obtained his Ph.D. in physiology there. Subsequently, he was recruited to Harvard Medical School as an Assistant Professor of Medicine. 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 Associate Director (Education and Training) Stanford Cardiovascular Institute