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Inflammation plays an important role in aortic dissection (AD). Macrophages are critically involved in the inflammation after aortic injury. Neuraminidases (NEUs) are a family of enzymes that catalyze the cleavage of terminal sialic acids from glycoproteins or glycolipids, which is emerging as a regulator of macrophage-associated immune responses. However, the role of neuraminidase 1 (NEU1) in pathological vascular remodeling of AD remains largely unknown. This study sought to characterize the role and identify the potential mechanism of NEU1 in pathological aortic degeneration. After β-aminopropionitrile monofumarate (BAPN) administration, NEU1 elevated significantly in the lesion zone of the aorta. Global or macrophage-specific NEU1 knockout (NEU1 CKO) mice had no baseline aortic defects but manifested improved aorta function, and decreased mortality due to aortic rupture. Improved outcomes in NEU1 CKO mice subjected to BAPN treatment were associated with the ameliorated vascular inflammation, lowered apoptosis, decreased reactive oxygen species production, mitigated extracellular matrix degradation, and improved M2 macrophage polarization. Furthermore, macrophages sorted from the aorta of NEU1 CKO mice displayed a significant increase of M2 macrophage markers and a marked decrease of M1 macrophage markers compared with the controls. To summarize, the present study demonstrated that macrophage-derived NEU1 is critical for vascular homeostasis. NEU1 exacerbates BAPN-induced pathological vascular remodeling. NEU1 may therefore represent a potential therapeutic target for the treatment of AD.

Recent studies have unveiled that myocardial hypertrophic preconditioning (HP), which is produced by de-banding (De-TAC) of short-term transverse aortic constriction (TAC), protects the heart against hypertrophic responses caused by subsequent re-constriction (Re-TAC) in mice. Although cardiac substrate metabolism is impaired in heart failure, it remains unclear about the role of HP-driven energetics in the development of cardiac hypertrophy. Here, we investigated energy metabolism, cardiac hypertrophy, and function following variational loading conditions, as well as their relationships in HP. Male C57BL/6J mice (10–12 weeks old) were randomly subjected to Sham, HP [TAC for 3days (TAC 3d), de-banding the aorta for 4 days (De-TAC 4d), and then re-banding the aorta for 4 weeks (Re-TAC 4W)], and TAC (TAC for 4 weeks without de-banding). Cardiac echocardiography, hemodynamics, and histology were utilized to evaluate cardiac remodeling and function. The mRNA expression levels of fetal genes (ANP and BNP), glucose metabolism-related genes (glut4, pdk4), and fatty acid oxidation-related genes (mcad, pgc1α, mcd, pparα) were quantitated by real-time quantitative PCR. Activation of hypertrophy regulators ERK1/2, a metabolic stress kinase AMP-activated protein kinase (AMPK), and its downstream target acetyl-coA carboxylase (ACC) were explored by western blot. Compared with TAC 4W mice, Re-TAC 4W mice showed less impairment in glucose and fatty acid metabolism, as well as less cardiac hypertrophy and dysfunction. Moreover, no significant difference was found in myocardial hypertrophy, fibrosis, and cardiac function in TAC 3d and De-TAC 4d groups compared with Sham group. However, glut4, pdk4, mcad, pgc1α, mcd, and pparα were all decreased, while AMPK and ACC were activated in TAC 3d and returned to Sham level in De-TAC 4d, suggesting that the change in myocardial energy metabolism in HP mice was earlier than that in cardiac structure and function. Collectively, HP improves energy metabolism and delays cardiac remodeling, highlighting that early metabolic improvements drive a potential beneficial effect on structural and functional restoration in cardiac hypertrophy.