Inhibition of smooth muscle cell migration by heme oxygenase I

Details Inhibition of smooth muscle cell migration by heme oxygenase I Inhibition of smooth muscle cell migration by heme oxygenase I

1999-08-20

2001-03-20

Schwartzman, Robert A. (Department: 1636)

Chemistry: molecular biology and microbiology

Measuring or testing process involving enzymes or...

Involving nucleic acid

C435S320100, C435S458000, C514S04400A, C536S023100

Reexamination Certificate

active

06203991

ABSTRACT:

BACKGROUND OF THE INVENTION
The role of inducible second messenger gases like carbon monoxide (CO) in the pathophysiology of cardiovascular disease are not clear to date (Wever, et al.,
Circulation
97,108-112, 1998; Cooke and Dzau,
Circulation
96, 379-382, 1997; Moncada, et al.,
Pharmacol.Rev
. 43, 109-142, 1997; Loscalzo, and Welch,
Progress in Cardiovascular Diseases
38, 87-104, 1995). The heme oxygenase system, that generates CO, consists of three isozymes identified so far: the inducible heme oxygenase I (HO-1), the constitutive expressed HO-2 and HO-3(Moncada, et al,
Pharmacol.Rev
.43, 109-142, 1997; McCoubrey et al.,
Eur.J.Biochem
247, 725-732, 1997; Maines, et al.,
J.Biol.Chem
. 261, 411-419, 1986; Shibahara et al.,
Proceedings of the National Academy of Sciences USA
240, 7865-7869, 1985; Rotenberg et al.,
J.Biol.Chem
. 265, 7501-7506, 1990), which all catalyze oxidation of heme into the biologically active molecules iron, biliverdin and CO.
The widespread expression of the heme oxygenases led to the hypothesis that the CO system may play other roles than maintaining heme homeostasis and indicate that CO may function as an important biological molecule in a second-messenger capacity. Indeed, CO has been shown to activate guanylyl cyclase by displacing the iron out of the plane of the porphoryrin ring of the heme protein. The formed cGMP then activates cGMP-dependent kinases. Recent studies now show that HO-derived carbon monoxide plays a physiological role in the regulation of local vascular smooth muscle tone and platelet function through activation of soluble guanylyl cyclase.
Hence, dysregulation of the CO system may play an eminent role in the pathogenesis of the vascular proliferative disorders, like atherosclerosis and restenosis. Smooth muscle cell proliferation and migration into the vascular lesion play a key role in the pathogenesis of these occlusive vascular proliferative disorders, which form the major delimiter to the long term success rate of percutaneous (coronary) transluminal procedures as well as of arterial and venous bypass grafting.
The physical and thrombotic events accompanying PTCA and CABG procedures result in a cascade of mitogen, chemotactic factor and inflammatory cytokine release which all promote local vascular smooth muscle cell and immune competent cell recruitment, and reentering and progression through the cell cycle. Activated medial smooth muscle cells proliferate and migrate in the damaged intima and synthesize extracellular matrix, including fibrin and collagen, leading to the (re)occlusion of the vessel. Pharmacological interventions to avert this process of aberrant vascular cell proliferation and migration has been largely unrewarding.
Thus, there exists a need for safe, effective methods of inhibiting vascular smooth muscle cell proliferation and migration into the lumen of the blood vessel following injury to the blood vessel.


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