Abstract
Acute cardiac rupture and adverse left ventricular (LV) remodeling causing heart failure are serious complications of acute myocardial infarction (MI). While cardio-hepatic interactions have been recognized, their role in MI remains unknown. We treated cultured cardiomyocytes with conditioned media from various cell types and analyzed the media by mass spectrometry to identify α1-microglobulin (AM) as an Akt-activating hepatokine. In mouse MI model, AM protein transiently distributed in the infarct and border zones during the acute phase, reflecting infiltration of AM-bound macrophages. AM stimulation activated Akt, NFκB, and ERK signaling and enhanced inflammation as well as macrophage migration and polarization, while inhibited fibrogenesis-related mRNA expression in cultured macrophages and cardiac fibroblasts. Intramyocardial AM administration exacerbated macrophage infiltration, inflammation, and matrix metalloproteinase 9 mRNA expression in the infarct and border zones, whereas disturbed fibrotic repair, then provoked acute cardiac rupture in MI. Shotgun proteomics and lipid pull-down analysis found that AM partly binds to phosphatidic acid (PA) for its signaling and function. Furthermore, systemic delivery of a selective inhibitor of diacylglycerol kinase α-mediated PA synthesis notably reduced macrophage infiltration, inflammation, matrix metalloproteinase activity, and adverse LV remodeling in MI. Therefore, targeting AM signaling could be a novel pharmacological option to mitigate adverse LV remodeling in MI.
Highlights
Acute myocardial infarction (MI) is a life-threatening coronary artery disease
Α1-microglobulin/bikunin precursor (AMBP) is a highly-conserved glycoprotein exclusively synthesized and secreted from the liver[14]. It is proteolytically processed into two different proteins: α1-microglobulin (AM) and bikunin (184 and 147 amino acids in human, respectively), which belong to the lipocalin family and the protease inhibitor family, respectively[15]
Using a mouse MI model, we demonstrate that AM treatment enhances MQ infiltration and cardiac fibroblasts (CFBs)/MQ-mediated inflammation while inhibiting fibrotic repair, resulting in acute cardiac rupture
Summary
Acute myocardial infarction (MI) is a life-threatening coronary artery disease. While reperfusion therapy in the acute phase has significantly improved survival rate[1], pharmacological intervention to mitigate cardiomyocyte necrosis has not been clinically evaluated, and serious complications, such as left ventricular (LV) free wall rupture, can occur in the acute phase of MI. A recent study has questioned the utility of AM as a universal antioxidant as administration fails to decrease non-heme-induced injury, but worsens renal injury both in vitro and in vivo[20] This controversy highlights our limited understanding of AM hepatokine function, receptor interaction, and the downstream signaling pathways affected during disease, during cardiovascular inflammation. A protein-lipid overlay assay and lipid pull-down assay indicate that AM interacts with phosphatidic acid (PA), a functionally diverse phospholipid found in the plasma membrane that is involved in the progression of multiple disorders Disruption of this interaction with PA synthesis inhibitors suggests that AM signaling is mediated by PA, and the administration of a selective inhibitor of PA synthesis had cardioprotective effects in mouse MI
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