Related Experiment Video
Updated: Mar 11, 2026
Perturbing Endothelial Biomechanics via Connexin 43 Structural Disruption
Published on: October 4, 2019
Amphiregulin attenuates sepsis-induced myocardial dysfunction by maintaining the localization of connexin43
Man Chen1, Shinnosuke Takamori1,2, Koichi Isayama3
1Department of Advanced Emergency and Disaster Medicine, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-Ku, Fukuoka, 812-8582, Japan.
Insights
Sepsis-induced myocardial dysfunction (SIMD) involves Connexin 43 (Cx43) changes. Amphiregulin (AREG) prevents SIMD by reducing Cx43 phosphorylation via p38 inhibition.
Area of Science:
- Cardiovascular Biology
- Molecular Medicine
- Sepsis Research
Background:
- Sepsis-induced myocardial dysfunction (SIMD) significantly increases mortality.
- Connexin 43 (Cx43) disruption is linked to cardiac dysfunction.
- The role of Cx43 localization in SIMD and the potential of Amphiregulin (AREG) are unexplored.
Purpose of the Study:
- To investigate the role of Cx43 in SIMD.
- To explore the preventive effects of AREG on SIMD.
- To elucidate the underlying molecular mechanisms.
Main Methods:
- Established a mouse model of SIMD using lipopolysaccharide (LPS).
- Administered AREG and assessed cardiac function via echocardiography and ECG.
- Analyzed Cx43 regulation, inflammatory markers, and signaling pathways in tissues and cardiomyocytes.
Main Results:
- LPS induced SIMD, reducing cardiac function and causing Cx43 disorganization.
- Cx43 phosphorylation at S368, mediated by p38 activation, was observed.
- AREG improved cardiac function, preserved Cx43 localization, and inhibited p38 phosphorylation.
Conclusions:
- Cx43 phosphorylation plays a key role in SIMD.
- AREG demonstrates preventive potential against SIMD.
- AREG's effects are linked to reduced p38 activation and decreased pS368-Cx43 phosphorylation, suggesting a novel therapeutic target.
Background:
Sepsis-induced myocardial dysfunction (SIMD) is a prevalent complication among septic patients, significantly worsening patient prognosis and elevating the mortality rate. Connexin 43 (Cx43), a pivotal cardiac gap junction protein, maintains cardiac function, and its disarrangement is closely linked to cardiac diseases. However, the role of Cx43 localization changes in SIMD remains unclear. Amphiregulin (AREG) was recently reported to promote the recovery of Cx43 disarrangements. This research aimed to explore the role of Cx43 in SIMD and the preventive potential of AREG.
Methods:
A mouse model of SIMD was induced using lipopolysaccharide (LPS) and treated with AREG. Cardiac function and electrical conduction were assessed using echocardiography and an electrocardiogram. Inflammatory responses, Cx43 regulation, and related signaling pathways were further investigated in serum and cardiac tissues. Relevant signal pathway analysis was investigated in cultured cardiomyocytes.
Results:
LPS administration significantly reduced cardiac ejection fraction and left ventricular fractional shortening, which were accompanied by disorganization, fragmentation, and lateralization of Cx43 at 6 h. These pathological alterations were associated with increased phosphorylation of pS368-Cx43, mediated by p38 activation. AREG pretreatment improved cardiac function and QRS interval, and preserved Cx43 localization at intercellular discs, along with pS368-Cx43 phosphorylation with reduction of p38 inhibition. Myocardial cell studies confirmed that AREG inhibited p38 phosphorylation, independent of AKT, in LPS-induced cardiac dysfunction.
Conclusion:
This study highlights the role of Cx43 phosphorylation in SIMD and demonstrates the preventive potential of AREG in SIMD, which is associated with a reduction in p38 activation and a decrease in the phosphorylation level of pS368-Cx43. These findings may provide a novel therapeutic target for SIMD.
