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Nicotine-pathological angiogenesis and genetic determinants

Institution: Stanford University
Investigator(s): John Cooke, M.D., Ph.D.
Award Cycle: 2002 (Cycle 11) Grant #: 11RT-0147 Award: $608,420
Subject Area: Cardiovascular Disease
Award Type: Research Project Awards
Abstracts

Initial Award Abstract
Atherosclerosis ("hardening of the arteries") leads to narrowing and blockage of blood vessels. Blockage of a vessel can lead to heart attack (if the narrowing is in a heart artery) or stroke(if the narrowing is in a brain vessel). Tobacco accelerates hardening of the arteries. Recently, there has been great excitement about a new approach to treating blockages. The body is capable of making small vessels around a blockage, a sort of "biological bypass". These biological bypasses provide some blood flow around a blockage, and can thereby prevent a heart attack, and relieve pain. There is now a much better understanding of the process by which these biological bypasses form. Indeed we have found growth factors that can accelerate the growth of biological bypasses. Some of these growth factors are now undergoing clinical trials to see if they will help people with blockages in their vessels.

We have been studying the process by which biological bypasses form. To our great surprise. we have found that nicotine accelerates the formation of biological bypasses. In two of our animal models, we have found that nicotine increases blood vessel formation 2-4 fold. The increased formation of these little bypasses improves blood flow in an animal model of vessel blockage.

This is an exciting and unexpected finding. It may shift how we think about tobacco-related diseases. It may lead to new therapies.

The growth of biological bypasses can be good, when they are improving blood flow to parts of the body supplied by blocked vessels. However, the growth of biological bypasses can be bad, such as when they are supplying a tumor, or allowing the growth of a plaque in the vessel (plaques need small vessels as they enlarge).

Perhaps some of tobacco's effects (to cause tumor, and to accelerate plaque growth) may be explained by the effect of nicotine to stimulate biological bypass formation. Indeed, we have found that nicotine accelerates the growth of blood vessels to tumors, and increases tumor growth. We have also found that nicotine accelerates the growth of tiny blood vessels into plaque, thereby accelerating plaque growth.

Now we plan to discover the genes that are responsible for the effect of nicotine. These studies may lead to new therapies to treat tumor and plaque.
Publications

Nicotine stimulates wound healing in diabetic mice.
Periodical: American Journal of Pathology Index Medicus:
Authors: Jacobi J, Jang JJ, Sundram U, Fajardo L, Cooke JP ART
Yr: 2002 Vol: 161 Nbr: 1 Abs: Pg: 97-104

Impaired nitric oxide synthase pathway in diabetes mellitus: role of asymmetric dimethylarginine and dimethylarginine dimethylaminohydrolase.
Periodical: Circulation Index Medicus:
Authors: Lin KY, Ito A, Asagami T, Tsao PS, Adimoolam S, Kimoto M, Tsuji H, Reaven G, Cooke JP ART
Yr: 2002 Vol: 106 Nbr: 8 Abs: Pg: 987-92

A novel angiogenic pathway mediated by non-neuronal nicotinic acetylcholine receptors.
Periodical: Journal of Clinical Investigation Index Medicus:
Authors: Heeschen C, Weis M, Cooke JP ART
Yr: 2002 Vol: 110 Nbr: 4 Abs: Pg: 527-536

Homocysteine impairs coronary microvasular dilator function in humans.
Periodical: Journal of American College Cardiology Index Medicus:
Authors: Tawakol A, Forgione MA, Stuehlinger M, Alpert NM, Cooke JP, et al. ART
Yr: 2002 Vol: 40 Nbr: 6 Abs: Pg: 1051-1058

Short polymers of arginine rapidly translocate into vascular cells: effects on nitric oxide synthesis.
Periodical: Circulation Index Medicus:
Authors: Uemura S, Rothbard J, Matsushita H, Tsao PS, Fathman CG, Cooke JP ART
Yr: 2002 Vol: 66 Nbr: 12 Abs: Pg: 1155-1160

Nicotine promotes arteriogenesis.
Periodical: Journal of American College Cardiology Index Medicus:
Authors: Heeschen C, Weis M, Cooke JP ART
Yr: 2003 Vol: 41 Nbr: 3 Abs: Pg: 489-496

NO and angiogenesis.
Periodical: Cardiovascular Research Index Medicus:
Authors: Cooke JP ART
Yr: 0 Vol: 4 Nbr: 4 Abs: Pg: 53-60

Nicotine strongly activates dendritic cell-mediated adaptive immunity - potential role for progression of atherosclerotic lesions.
Periodical: Circulation Index Medicus:
Authors: Aicher A, Heeschen C, Mohaupt M, Cooke JP, Zeiher AM, Dimmeler S ART
Yr: 2003 Vol: 107 Nbr: 4 Abs: Pg: 604-11

Second hand smoke stimulates tumor angiogernesis and growth.
Periodical: Cancer Cell Index Medicus:
Authors: Zhu B, Heeschen C, Sievers RE, Karliner JS, Parmley WW, Glantz SA, Cooke JP ART
Yr: 2003 Vol: 4 Nbr: 3 Abs: Pg: 191-6

Nicotine and angiogenesis: a new paradigm for tobacco-related diseases.
Periodical: Annals of Medicine Index Medicus:
Authors: Cooke JP, Bitterman H ART
Yr: 2004 Vol: 36 Nbr: 1 Abs: Pg: 33-40

NOS inhibition accelerates atherogenesis: Reversal by exercise.
Periodical: American Journal of Physiology, Heart and Circulatory Physiology Index Medicus:
Authors: Niebauer J, Maxwell AJ, Lin PS, Heidari S, Tsao P, Cooke JP ART
Yr: 2003 Vol: Nbr: Abs: Pg:

Flow-responsive remodeling after angioplasty is enhanced by high cholesterol diet. Prevention with pyrrolidine dithiocarbamate.
Periodical: Atherosclerosis Index Medicus:
Authors: Ward MR, Tsao PS, Herity NA, Cooke JP, Yeung AC ART
Yr: 2003 Vol: 168 Nbr: 2 Abs: Pg: 333-41

DDAH regulates NO synthesis: Genetic and physiological evidence.
Periodical: Circulation Index Medicus:
Authors: Dayoub H, Achan V, Adimoolam S, Jacobi J, Stuehlinger M, Wang B, Cooke AJ, et al ART
Yr: 2003 Vol: 108 Nbr: Abs: Pg: 1043-1048

Discordant effects of a soluble VEGF receptor on wound healing and angiogenesis.
Periodical: Gene Therapy Index Medicus:
Authors: Jacobi J, Tam BYY, Sundram U, von Degenfeld G, Blau HM, Kuo CJ, Cooke JP ART
Yr: 2004 Vol: 11 Nbr: 3 Abs: Pg: 302-9

Developmental endothelial locus-1 (Del-1): a novel angiogenic protein. Its role in ischemia circulation.
Periodical: Circulation Index Medicus:
Authors: Ho H-K V, Jang JJ, Kaji S, Spektor G, Fong A, Yang P. Hu RS, Cooke JP, et al ART
Yr: 2004 Vol: 109 Nbr: 10 Abs: Pg: 1314-9

Asymmetric dimethylarginine (ADMA): A key regulator of nitric oxide synthase.
Periodical: Atherosclerosis Supplement Index Medicus:
Authors: Boger RH, Vallance P, Cooke JP ART
Yr: 2003 Vol: 4 Nbr: 4 Abs: Pg: 1-3

Cardiac allograft vasculopathy and dysregulation of the nitric oxide synthase pathway.
Periodical: Arteriosclerosis, Thrombosis, and Vascular Biology Index Medicus:
Authors: Weis M, Cooke JP ART
Yr: 2003 Vol: 23 Nbr: 4 Abs: Pg: 567-75

Asymmetrical dimethylarginine: the uber marker?
Periodical: Circulation Index Medicus:
Authors: Cooke JP ART
Yr: 2004 Vol: 109 Nbr: 15 Abs: Pg: 1813-8