Role of Nitric Oxide in Cardiovascular Disorders - Applications of Biotechnology in Cardiovascular Therapeutics - page 69

immature angiogenic sprouts (Yu et al. 2005 ). The genetic loss of eNOS in mice
impairs vascular endothelial growth factor (VEGF) and ischemia-initiated blood
flow recovery resulting in critical limb ischemia. An experimental study has shown
that the impaired neovascularization in mice lacking eNOS is related to a defect in
VEGF-induced progenitor cell mobilization (Aicher et al. 2003 ). Intravenous infu-
sion of wild-type progenitor cells, but not bone marrow transplantation, rescued the
defective neovascularization. These findings indicate that eNOS expressed by bone
marrow stromal cells influences recruitment of stem and progenitor cells. This may
contribute to impaired regeneration processes in ischemic heart disease patients,
who are characterized by a reduced systemic NO bioactivity.
During the last two decades it has become apparent that a variety of diseases are
associated with an impairment of endothelium-dependent NO activity. One of the
major causes is believed to be an increased production of reactive oxygen species,
in particular superoxide, which has been shown to interfere with many steps of the
NO-cyclic guanosine monophosphate (cGMP) pathway. This phenomenon has
been found in diverse conditions such as atherosclerosis, hypertension, diabetes,
hypercholesterolemia, heart failure, and cigarette smoking.
African Americans suffer from cardiovascular diseases at a rate about five times
higher than the rest of the US population. The culprit is a serious deficiency of NO
(Kalinowski et al. 2004 ). ONOO- plays a central role in vascular pathophysiology.
The differences in endothelial NO/O 2 -/ONOO- metabolism may highlight the
potential predisposition to endothelial dysfunction and cardiovascular complica-
tions prevalent in blacks. NO/O 2 -/ONOO- nanosensors were used to record eNOS
from endothelial cell isolated from blacks and whites. Compared to whites, endothe-
lial cells from blacks elicited reduced release of bioactive NO with an accompany-
ing increase in the release of both O 2 - and ONOO-. The greater potency of NO
production because of eNOS upregulation in blacks is associated with a decrease in
the NO bioavailability. This is due to increased NO degradation by excess O 2 - pro-
duced primarily by two enzymatic sources: NAD(P)H-oxidase and uncoupled
eNOS. Compared with whites, the steady-state NO/O 2 -/ONOO- balance in endothelial
cells from blacks is kept closer to the redox states characteristic for the endothelium-
impaired function disorders. This may explain the differences in racial predisposi-
tion to the endothelium dysfunction during ongoing vascular disturbances with the
hallmark of enhanced NO inactivation within the endothelium by oxidative stress.
This observation opens the door for the development of new drugs designed specifi-
cally to maintain healthy levels of NO in the cardiovascular system.
Role of nNOS in Cardiac Arrhythmia and Sudden Death
NO derived from nNOS facilitates cardiac vagal neurotransmission and bradycar-
dia in vitro. Pre-/post-ganglionic synapse is considered to be a site for NO-mediated
facilitation of vagal bradycardia. Functional gene expression induced with adeno-
viral vectors may provide a novel intervention to acutely modulate the neural con-
trol of cardiac excitability.
Extremes of the electrocardiographic QT interval, a measure of cardiac repolar-
ization, are associated with increased cardiovascular mortality. A gene called