Role of Nitric Oxide in Cardiovascular Disorders - Applications of Biotechnology in Cardiovascular Therapeutics - page 71

ment of atherosclerotic lesions results in the formation of lipid-laden plaques that
are prone to fissure, ulceration, and rupture. Thrombosis resulting from the plaque
rupture in the coronary arteries plays a pivotal role in the progression from athero-
sclerosis to myocardial infarction. Hence, NOS therapy might be expected to
improve endothelium-dependent vasodilation, reverse the altered endothelial redox
state, suppress smooth muscle cell proliferation, and stabilize vulnerable plaques.
Ingestion of certain NO-boosting substances, including L-arginine, L-citrulline, and
antioxidants has been shown to reduce oxidative stress and reverse the progression
of atherosclerosis in rabbits fed a high-cholesterol diet (Hayashi et al. 2005 ). This
approach may have clinical utility in the treatment of atherosclerosis in humans.
The impaired endothelium-dependent vasodilatory response (EDR) has been
demonstrated in vessels exposed to hypercholesterolemia and atherosclerosis. The
extent of impairment serves as a predictor of future progression of atherosclerosis.
As to the mechanisms of impaired EDR, increased production of superoxide is impor-
tant and is linked to eNOS. eNOS becomes dysfunctional and produces superoxide
rather than NO under conditions in which vascular tissue levels of tetrahydrobiopterin
(BH 4 ), a cofactor for eNOS, are deficient or lacking. Dysfunctional eNOS is closely
implicated in the endothelial dysfunction represented by impaired EDR in various
vascular disorders including atherosclerosis. Experimental studies in vitro reveal
that NO from eNOS constitutes as an anti-atherogenic molecule. In eNOS-knockout
mice, eNOS deficiency augments atherosclerotic lesion formation, although the
effects may be partly due to the associated hypertension. However, in eNOS-transgenic
mice (eNOS-Tg) crossbred with apolipoprotein E-deficient mice (apoE-KO/eNOS-Tg),
the accelerated lesion formation in association with increased superoxide produc-
tion from vessels was comparable to that in apoE-KO mice (Kawashima 2004 ).
Chronic administration of exogenous BH 4 or overexpression of GTPCH-1, a rate
limiting enzyme for BH 4 synthesis, restored the lesion to the levels comparable to
apoE-KO mice. Therefore, eNOS may have two faces in the pathophysiology of
atherosclerosis depending on tissue BH 4 levels.
Role of NO in Cardiopulmonary Disorders
Red blood cells (RBCs) act as O 2 -responsive transducers of vasodilator and vaso-
constrictor activity in lungs and tissues by regulating the availability of NO.
Vasodilation by RBCs is impaired in diseases characterized by hypoxemia. The
extent to which RBCs constrict versus dilate vessels is, at least partly, controlled by
a partitioning between NO bound to heme iron and to Cysb93 thiol of Hb. Hemes
sequester NO, whereas thiols deploy NO bioactivity. Specific micropopulations of
NO-liganded Hb could support the chemistry of S-nitrosohemoglobin (SNO-Hb)
formation. By using nitrite as the source of NO, it was demonstrated that a microp-
opulation of a heme-NO species, with spectral and chemical properties of Fe 3 NO,
acts as a precursor to SNO-Hb formation, accompanying the allosteric transition
of Hb to the R state (Angelo et al. 2006 ). At physiological concentrations of nitrite