Hepatokine α1-Microglobulin Signaling Exacerbates Inflammation and Disturbs Fibrotic Repair in Mouse Myocardial...

Area of Science:

• Cardiovascular Biology
• Hepatology
• Immunology

Background:

• Acute myocardial infarction (MI) can lead to severe complications like cardiac rupture and heart failure due to adverse left ventricular (LV) remodeling.
• The role of cardio-hepatic interactions, particularly liver-secreted factors, in the context of MI pathophysiology remains largely unexplored.

Purpose of the Study:

• To investigate the role of liver-secreted factors in the cardiac response to MI.
• To identify specific hepatokines involved in adverse LV remodeling and cardiac rupture post-MI.
• To explore potential therapeutic targets for mitigating MI complications.

Main Methods:

• Mass spectrometry analysis of conditioned media identified alpha-1-microglobulin (AM) as an Akt-activating hepatokine.
• A mouse MI model was used to assess AM distribution, macrophage infiltration, and inflammatory signaling.
• AM signaling pathways (Akt, NFκB, ERK) and interactions with phosphatidic acid (PA) were investigated.
• Pharmacological inhibition of diacylglycerol kinase α-mediated PA synthesis was evaluated.

Main Results:

• AM protein was detected in infarct and border zones of MI hearts, associated with macrophage infiltration.
• AM stimulation enhanced inflammation, macrophage migration/polarization, and matrix metalloproteinase 9 expression, while inhibiting fibrogenesis.
• Intramyocardial AM administration worsened cardiac repair and provoked acute cardiac rupture.
• AM binds to phosphatidic acid (PA) for signaling; inhibiting PA synthesis reduced inflammation and adverse LV remodeling.

Conclusions:

• Alpha-1-microglobulin (AM) plays a detrimental role in the acute phase of myocardial infarction, promoting inflammation and impairing wound healing.
• AM signaling, partly mediated by phosphatidic acid, contributes to adverse left ventricular remodeling and cardiac rupture.
• Targeting AM signaling represents a potential novel therapeutic strategy to prevent heart failure following MI.