Biomedical Engineering Reference
In-Depth Information
ascorbic acid, whereas protein nitration was increased. Carnes
et al
. (2001)
showed that protein nitration among other processes accounts for electrical
remodeling. Nitration and carbonylation of structural proteins especially alter
Ca
2+
handling of the endocardial cell. Abnormal calcium handling, however,
not only changes electrophysiological properties, but also impairs mitochondrial
function and thus myocardial energetics. In the cardiovascular system, voltage-
activated Ca
2+
channels are essential for the generation of normal cardiac rhythm,
for induction of rhythm propagation through the atrioventricular node, and also
for the contraction of the atrial and ventricular muscle. In diseased myocardium,
calcium channels can contribute to abnormal impulse generation and cardiac
arrhythmias. Under physiological state, mitochondria serve their well-known
role in generation of adenosine triphosphate (ATP) by oxidative phosphorylation.
Massive Ca
2+
inl ux into the cytosol and subsequent Ca
2+
sequestration by
mitochondria result in marked alterations of mitochondrial morphology in atrial
tissue of patients with AF (Schild
et al.
2006). Recently, using two rapid pacing
models of
in vitro
dif erentiated P19 cardiomyocytes and of human atrial tissue
slices, we demonstrated that tachycardia is associated with mitochondrial swelling,
and impairment of mitochondrial ATP production as evidenced by decreased
endogenous respiration in combination with decreased ATP levels in intact cells
(Schild
et al.
2006). Inhibition of Ca
2+
inward current with the calcium receptor
antagonist verapamil protected against hypertrophic response and oxidative
stress. Verapamil thus ameliorated morphological changes and dysfunction of
mitochondria. Moreover, dysfunctional mitochondria seemed to contribute to
signaling pathways aggravating oxidative stress and initiating the inl ammatory
status in atrial tissue. Data from our studies suggest that non-physiological
Ca
2+
entry is the primary trigger for mitochondrial dysfunction and oxidative
stress within myocytes during tachycardia (Bukowska
et al.
2008). h e i nding
that calcium receptor antagonists exert a protective ef ect on oxidative stress is
supported by other studies. h ey showed that mibefradil, which blocks L-type and
T-type Ca
2+
channels, and verapamil prevent the oxidation of cellular constituents
and have cytoprotective ef ects.
Besides oxidative stress induced by changes in intracellular Ca
2+
handling, Kim
et al.
(2005) have identii ed the NADPH oxidase to be the major source of ROS
in the atrial system, whereas mitochondrial oxidase contribution is rather low
(Schild
et al.
2006). In AF, NADPH oxidase activity was shown to be increased
(Dudley
et al.
2005). Angiotensin II (Ang II) coupling of the AT1R was shown to
stimulate the generation of ROS by induction of NADPH oxidase. AF is associated
with a strong activation of the atrial renin-angiotensin-system (RAS), including
induction of AngII and AngII-generating angiotensin-converting enzyme (ACE).
Besides induction of NADPH oxidases, AngII binding to the G-protein-linked
AT1R induces a cascade of phosphorylation that activates mitogen-activated
protein kinases, leading to cell proliferation and cellular hypertrophy. h e two
major contributors to oxidative stress during AF are depicted in Fig. 3.
