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SHS Exacerbates cerebral ischemia: endothelial mechanisms

Institution: Stanford University
Investigator(s): John Cooke, M.D., Ph.D.
Award Cycle: 2005 (Cycle 14) Grant #: 14RT-0169 Award: $654,849
Subject Area: Cardiovascular Disease
Award Type: Research Project Awards

Initial Award Abstract
Stroke is a devastating illness. Stroke is a form of cardiovascular disease that blocks vessels supplying blood to the brain. Stroke, the leading cause of long-term disability in the U.S., kills about 160,000 Americans every year, and was the third leading cause of death, behind heart disease and cancer. (In Japan, it is the major cause of cardiovascular death.)

Stroke refers to brain damage due to inadequate blood flow. Common causes of stroke include atherosclerosis (hardening of the artery) affecting the arteries to the brain. A common cause of hardening of the arteries is tobacco use. Second hand smoke (SHS; passive smoking, due to the use of tobacco by others) is also known to damage arteries.

In this study we will determine whether SHS causes changes in the arteries of the brain that worsen any sudden reductions in blood flow. Furthermore, we will determine if SHS impairs the ability of new blood vessels to grow into the brain (in a process called angiogenesis).

Blood flow is regulated by many substances in the body. One of the most potent of this is nitric oxide (NO). We have found that NO is one of the strongest vasodilators (substances that relax the vessels to increase blood flow). In addition, NO is critical for the process of angiogenesis. Deficiency of NO reduces blood flow and impairs the ability of the body to regenerate blood vessels. A deficiency of NO production occurs in people who have elevated levels of ADMA (asymmetric dimethylarginine). This substance is increased by high cholesterol, high blood pressure, high blood sugar, and other conditions that can cause hardening of the arteries. We will determine if SHS can increase blood levels of ADMA, and thereby make strokes worse. We will also determine if ADMA impairs the ability of the body to make new blood vessels.

Another substance that regulates blood flow and blood vessel formation is acetylcholine. This substance is produced by the brain, and by the blood vessels. Acetylcholine can stimulate the brain (for thinking) and can stimulate blood vessels (to increase blood flow, and to cause angiogenesis). Notably, the nicotine in tobacco smoke can hijack the brain (causing addiction), and the blood vessels (initially causing vasodilation and angiogenesis). However, we have data that long-term exposure to tobacco smoke can impair the ability of the blood vessels to relax, and to generate new blood vessels. We therefore believe, and will try to confirm in this study, that long term exposure to SHS inhibits vasodilation and angiogenesis, and thereby impairs stroke.

These studies may lead to new therapies to prevent or treat stroke, based on our growing knowledge of how to control blood vessel relaxation (and blood flow) and to regulate the development of new blood vessels (angiogenesis).

DDAH Overexpression suppresses graft coronary artery disease in murine cardiac allografts
Periodical: Circulation Index Medicus:
Authors: Tanaka M, Sydow K, Gunawan F, Jacobi J, Tsao PS, Robbins RC and Cooke JP ART
Yr: 2005 Vol: 11 Nbr: Abs: Pg: 1549-56

abnormal cardiovascular resonse to exercise in patients with peripheral arterial disease
Periodical: J Vasc Nurs Index Medicus:
Authors: Oka RK, Altman M, Giacomini JC, Szuba A, Cooke JP ART
Yr: 2005 Vol: 23 Nbr: 4 Abs: Pg: 130-136

Homocysteine-induced vascular dysregulation is mediated by the NMDA receptor
Periodical: Vascular Medicine Index Medicus:
Authors: Qureshi L, Chen H, Brown AT, Fitzgerald R, Wang Y , Breckenridge J, Kazi R, Crocker AJ ART
Yr: 2005 Vol: 10 Nbr: 3 Abs: Pg: 215-223

ADMA increase arterial stiffness and decreases cerebral blood flow in man
Periodical: Stroke Index Medicus:
Authors: Kielstein JT, Donnerstag F, Gasper S, Menne J, Kielstein A, Martens-Lobenhoffer J, Scalera ART
Yr: 2006 Vol: Nbr: Abs: Pg:

Insulin resistance potential role of the endogenous nitric oxide synthase inhibitor ADMA
Periodical: Vascular Medicine Index Medicus:
Authors: Sydow K, Mondon CE and Cooke JP ART
Yr: 0 Vol: Nbr: 10 Abs: Pg: 35-43

Its role in Vascular disease
Periodical: Vascular Medicine Index Medicus:
Authors: Cooke JP ART
Yr: 2005 Vol: 10 Nbr: Abs: Pg: S11-17

Mechanisms of raynaud's disease
Periodical: Vascular Medicine Index Medicus:
Authors: Cooke Jp Marshall J ABS
Yr: 2005 Vol: 10 Nbr: 4 Abs: Pg: 293-307

Asymmetric Dimethylarginine ADMA an endogenous inhibitor of angiogenesis
Periodical: European Journal of Clinical Pharmacol Index Medicus:
Authors: Cooke JP ART
Yr: 2006 Vol: 13 Nbr: Abs: Pg: 115-121

Mecamylamine suppresses basal and nicotine-stimulated choroidal neovascularization.
Periodical: Investigative Ophthalmology and Visual Science Index Medicus:
Authors: Kiuchi, Matsuoka, Wu, Lima, Silver, Kengatharan, Verghese, Yokoi, Khu, Cooke, Campochiar ART
Yr: 2008 Vol: 49 Nbr: 4 Abs: Pg: 1705-1711

Dimethylarginine dimethylaminohydrolase enhances insulin sensitivity.
Periodical: Arteriosclerosis, Thrombosis, and Vascular Biology Index Medicus:
Authors: Sydow K, Nondon CE, Schrader J, Konishi H, Cooke JP ART
Yr: 2008 Vol: 28 Nbr: 4 Abs: Pg: 692-697

Overexpression of dimethylarginine dimethylaminohydrolase inhibits ADMA-induced endothelial dysfunction in cerebral circulation.
Periodical: Stroke Index Medicus:
Authors: Sayoub H, Rodionov R, Lynch C, Cooke JP, arning E, Bottiglierie T, Lentz SR, Faraci FM ART
Yr: 2008 Vol: 39 Nbr: Abs: Pg: 180-184

Endothelial nicotinic acetylcholine receptors and angiogenesis.
Periodical: Trends in Cardiovascular Medicine Index Medicus:
Authors: Cooke JP, Ghebremariam YT ART
Yr: 2008 Vol: 18 Nbr: 7 Abs: Pg: 247-253

Murine moderlof hindimb ischemia.
Periodical: Journal of Visualized Experiments Index Medicus:
Authors: Niiyama H, Huang NF, Rollons M, Cooke JP ART
Yr: 2009 Vol: 21 Nbr: 23 Abs: Pg: pii:1035

Embryonic stem cell-derived endothelial cells for treatment of hindlimb ischemi.
Periodical: Journal of Visualized Experiments Index Medicus:
Authors: Huang NF, Niiyama H, De A, Gambhir SS, Cooke JP ART
Yr: 2009 Vol: 23 Nbr: 23 Abs: Pg: pii 1034

Cholinergic modulation of angiogenesis: Role of the a7 nicotinic acetylcholine receptor. [Epub ahead of print]
Periodical: Journal of Cellular Biochemistry Index Medicus:
Authors: Wu J, Chruscinski A, deJesus Perez V, Singh H, Pitsiouni M, Rabinovitch M, Utz P, Cooke JP ART
Yr: 2009 Vol: Nbr: Abs: Pg:

Chronic exposure to nicotine impairs cholinergic angiogenesis.
Periodical: Vascular Medicine Index Medicus:
Authors: Konshi H, Wu J. Cooke JP ART
Yr: 2009 Vol: Nbr: Abs: Pg: