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Abstract 15068: Connexin43 Concerns Arrhythmias Through Changes in Mitochondrial Ca 2+ and ROS
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Introduction:
Connexin43 (Cx43) is a connexin that forms gap junctions in hearts and exists as hemichannels in the inner mitochondrial membrane (mCx43). It is still unknown whether mCx43 is involved in the occurrence of arrhythmias. Thus, we examined whether deficiency of Cx43 increases arrhythmias and what roles mitochondrial Ca
2+
and ROS play in the occurrence of arrhythmias.
Methods:
Cardiac-specific Cx43-deficient (
Cx43
-/-
) mice were generated by crossing
Cx43
flox/flox
mice with α-myosin heavy chain
cre
+/-
mice. The resulting offspring,
Cx43
-/-
mice and their littermates (
Cx43
+/+
mice), were used. Trabeculae were dissected from mouse hearts. Force was measured with a strain gauge, mitochondrial Ca
2+
with rhod-2, and mitochondrial ROS with MitoSox Red. The spatial distribution of rhod-2 and MitoSox Red imaged with confocal microscopy was similar to that of MitoTracker Green within trabeculae, meaning that rhod-2 and MitoSox Red are loaded within mitochondria. MitoSox Red fluorescence was measured before (Fl) and after the addition of 10 mM H
2
O
2
(FlH
2
O
2
), and the ratio of Fl to FlH
2
O
2
was calculated. To estimate arrhythmogenesis, the minimal extracellular Ca
2+
concentration (Cao), at which arrhythmias were induced by electrical stimulation (0.3-s stimulus intervals for 30 s), was determined (Cao
min
).
Results:
Cx43
-/-
mice died within 8 weeks (p<0.01). Cx43 was present in the inner mitochondrial membrane in
Cx43
+/+
mice but not in
Cx43
-/-
mice. In
Cx43
-/-
mice, rhod-2 fluorescence was higher than that of
Cx43
+/+
mice (n=7, p<0.01), while developed force of
Cx43
-/-
mice was similar to that of
Cx43
+/+
mice. The Cao
min
in
Cx43
-/-
mice was lower than that in
Cx43
+/+
mice (n=5, p<0.01), suggesting that
Cx43
-/-
mice shows increased arrhythmogenesis. In
Cx43
-/-
mice, Ru360 (5 μM), a mitochondrial calcium uniporter inhibitor, increased the Cao
min
, that is, decreased arrhythmogenesis, with decreases in rhod-2 and MitoSox Red fluorescence (n=6, p<0.05). Antioxidant peptide SS-31 (50 μM) and N-acetyl-L-cysteine (1 mM) increased the Cao
min
in
Cx43
-/-
mice (n=5, p<0.05), and the ratio of Fl to FlH
2
O
2
in
Cx43
-/-
mice was larger than that in
Cx43
+/+
mice.
Conclusions:
Deficiency of Cx43 increases arrhythmogenesis with increases in mitochondrial Ca
2+
and ROS.
Ovid Technologies (Wolters Kluwer Health)
Title: Abstract 15068: Connexin43 Concerns Arrhythmias Through Changes in Mitochondrial Ca
2+
and ROS
Description:
Introduction:
Connexin43 (Cx43) is a connexin that forms gap junctions in hearts and exists as hemichannels in the inner mitochondrial membrane (mCx43).
It is still unknown whether mCx43 is involved in the occurrence of arrhythmias.
Thus, we examined whether deficiency of Cx43 increases arrhythmias and what roles mitochondrial Ca
2+
and ROS play in the occurrence of arrhythmias.
Methods:
Cardiac-specific Cx43-deficient (
Cx43
-/-
) mice were generated by crossing
Cx43
flox/flox
mice with α-myosin heavy chain
cre
+/-
mice.
The resulting offspring,
Cx43
-/-
mice and their littermates (
Cx43
+/+
mice), were used.
Trabeculae were dissected from mouse hearts.
Force was measured with a strain gauge, mitochondrial Ca
2+
with rhod-2, and mitochondrial ROS with MitoSox Red.
The spatial distribution of rhod-2 and MitoSox Red imaged with confocal microscopy was similar to that of MitoTracker Green within trabeculae, meaning that rhod-2 and MitoSox Red are loaded within mitochondria.
MitoSox Red fluorescence was measured before (Fl) and after the addition of 10 mM H
2
O
2
(FlH
2
O
2
), and the ratio of Fl to FlH
2
O
2
was calculated.
To estimate arrhythmogenesis, the minimal extracellular Ca
2+
concentration (Cao), at which arrhythmias were induced by electrical stimulation (0.
3-s stimulus intervals for 30 s), was determined (Cao
min
).
Results:
Cx43
-/-
mice died within 8 weeks (p<0.
01).
Cx43 was present in the inner mitochondrial membrane in
Cx43
+/+
mice but not in
Cx43
-/-
mice.
In
Cx43
-/-
mice, rhod-2 fluorescence was higher than that of
Cx43
+/+
mice (n=7, p<0.
01), while developed force of
Cx43
-/-
mice was similar to that of
Cx43
+/+
mice.
The Cao
min
in
Cx43
-/-
mice was lower than that in
Cx43
+/+
mice (n=5, p<0.
01), suggesting that
Cx43
-/-
mice shows increased arrhythmogenesis.
In
Cx43
-/-
mice, Ru360 (5 μM), a mitochondrial calcium uniporter inhibitor, increased the Cao
min
, that is, decreased arrhythmogenesis, with decreases in rhod-2 and MitoSox Red fluorescence (n=6, p<0.
05).
Antioxidant peptide SS-31 (50 μM) and N-acetyl-L-cysteine (1 mM) increased the Cao
min
in
Cx43
-/-
mice (n=5, p<0.
05), and the ratio of Fl to FlH
2
O
2
in
Cx43
-/-
mice was larger than that in
Cx43
+/+
mice.
Conclusions:
Deficiency of Cx43 increases arrhythmogenesis with increases in mitochondrial Ca
2+
and ROS.
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