Biomedical Engineering Reference
In-Depth Information
-alanine-histidine) complexes
with various heavy metals such as Zn
2
+
cation. It has anti-oxidative activity.
However, it abounds much more in skeletal muscles than in the myocardium [
638
].
Thiol is responsible for about 30% of the Zn
2
+
-buffering capacity and contributes
to redox buffer capacity. In cardiomyocytes, [Zn
2
+
]
i
can be greatly increased by
thiol-reactive oxidants [
638
].
In cardiomyocytes during the excitation-contraction cycle in physiological
conditions, Zn
2
+
sparks are controlled by changes in intracellular free Ca
2
+
[
638
].
They result mainly from ionic exchange on intracellular binding sites; this process
is highly sensitive to the oxidative state and pH inside the cell. In pathophysio-
logical conditions, free Zn
2
+
cation can contribute to oxidant-induced alterations
of excitation-contraction coupling. An optimal intracellular Zn
2
+
/Ca
2
+
ratio in
cardiomyocytes, particularly in mitochondria, must be preserved to avoid oxidative
stress.
In addition to metallothioneins, carnosine (or
β
6.6.5
Cyclic Adenosine Monophosphate
Cyclic adenosine monophosphate, a mediator of the sympathetic system, operates
via cyclic nucleotide pacemaker channel as well as protein kinase-A and RapGEF3
and RapGEF4
70
to regulate the excitation-contraction coupling.
Under
-adrenergic stimulation, protein kinase-A modulates cardiac contrac-
tility via intracellular Ca
2
+
fluxes, as it targets sarcolemmal Ca
V
1.2a channel
and sarcoplasmic reticulum ryanodine receptor. In addition, PKA phosphorylates
troponin-I, thereby reducing myofilament Ca
2
+
sensitivity and accelerating relax-
ation. Furthermore, it phosphorylates myosin-binding protein-C, in addition to titin.
Activators RapGEF3 and RapGEF4 are guanine nucleotide-exchange factors
for Rap1 and Rap2 GTPases. Protein RapGEF3 is highly expressed in the heart.
Unlike PKA, it decreases the amount of Ca
2
+
released by the sarcoplasmic reticu-
lum, hence reducing Ca
2
+
transient amplitude, enhances myofilament sensitivity
to Ca
2
+
, and increases cell shortening [
639
]. It provokes phosphorylation of
cardiac troponin-I and myosin-binding protein-C by protein kinase-C and Ca
2
+
-
calmodulin-dependent kinase CamK2.
β
70
A.k.a. exchange proteins directly activated by cAMP EPAC1 and EPAC2, respectively.
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