Amphiregulin attenuates sepsis-induced myocardial dysfunction by maintaining the localization of connexin43.

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 p(S368)-Cx43, mediated by p38 activation. AREG pretreatment improved cardiac function and QRS interval, and preserved Cx43 localization at intercellular discs, along with p(S368)-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 p(S368)-Cx43. These findings may provide a novel therapeutic target for SIMD.