Biomedical Engineering Reference
In-Depth Information
6.6.6
S100 Protein
Protein S100a1
71
is expressed in the myocardium, where it interacts with contractile
filaments and proteins of the sarcoplasmic reticulum (titin, SERCA, phospho-
lamban, and ryanodine channel). Calcium-binding protein S100a1 increases Ca
2
+
release from the sarcoplasmic reticulum by interacting with ryanodine channels. It
also contributes to the regulation of Ca
2
+
-induced Ca
2
+
-release.
Cardiomyopathies are associated with altered S100 protein levels. Protein
S100a1 is upregulated in right ventricular hypertrophy that is an adaptation
to a higher load [
642
] and downregulated in end-stage heart failure [
643
].
Administration of the S100A1 gene restores the contractile function of the failing
myocardium [
644
].
72
Heart failure is characterized by a decrease in calcium removal into the sarcoplas-
mic reticulum associated with SERCA2 activity and dysregulated calcium release
from the sarcoplasmic reticulum via ryanodine channels (Fig.
5.14
). Many types of
heart failure are associated with downregulation of SERCA2 expression, impaired
SERCA2-phospholamban ratio, and decreased phosphorylated phospholamban.
Heart failure can therefore be stopped and even reversed by correcting sarcoplasmic
reticulum calcium release and storage (SR Ca
2
+
cycling). Inhibition of phospholam-
ban enhances Ca
2
+
uptake in the sarcoplasmic reticulum and reduces heart failure
in several animal models of dilated cardiomyopathy and postmyocardial infarction
chronic heart failure [
416
].
6.6.7
Nervous Influences
Adrenergic signaling in the myocardium contributes to the positive control of the
heart rate (chronotropy
+
), contraction strength (inotropy
+
), and relaxation rate
(lusitropy
) by changes in levels of intracellular calcium ions or modifications
in sensitivity of regulatory proteins to calcium ions. Inotropic effects are due to
increased Ca
2
+
current and greater availability of stored Ca
2
+
ions. Sympathetic
control of the heart via
+
-adrenergic stimulation regulates Ca
2
+
handling by
β
71
Multifunctional proteins of the S100 category are diversified according to the structure, ion-
binding property (Ca
2
+
,Zn
2
+
,orCu
2
+
), spatial distribution in the intra- or extracellular space,
and ability to homo- and heterodimerize [
640
]. Several S100 proteins (S100a4, S100a8-S100a9,
S100a12-S100a13, and S100b) are secreted and have cytokine-like functions, as they interact with
the receptor for advanced glycation end (RAGE) products of the immunoglobulin superfamily.
Protein S100a4 has angiogenic effects [
641
].
72
Adenovirus-mediated S100A1 gene delivery normalizes S100a1 protein expression in a postin-
farction rat heart failure model and reverses contractile dysfunction of failing myocardium.
Moreover, S100A1 gene transfer decreases elevated [Na
+
]
i
to levels detected in non-failing
cardiomyocytes and restores energy supply in failing cardiomyocytes.
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