Cardiac Resident Macrophage-Derived Legumain Improves Cardiac Repair by Promoting Clearance and Degradation of Apoptotic Cardiomyocytes After Myocardial Infarction.

BACKGROUND: Cardiac resident macrophages are self-maintaining and originate from embryonic hematopoiesis. After myocardial infarction, cardiac resident macrophages are responsible for the efficient clearance and degradation of apoptotic cardiomyocytes (efferocytosis). This process is required for inflammation resolution and tissue repair; however, the underlying molecular mechanisms remain unknown. Therefore, we aimed to identify the mechanisms of the continued clearance and degradation of phagolysosomal cargo by cardiac resident macrophages during myocardial infarction. METHODS: Multiple transgenic mice such as Lgmn-/-, LgmnF/F; LysMCre, LgmnF/F; Cx3cr1CreER, LgmnF/F; LyveCre, and cardiac macrophage Lgmn overexpression by adenovirus gene transfer were used to determine the functional significance of Lgmn in myocardial infarction. Immune cell filtration and inflammation were examined by flow cytometry and quantitative real-time polymerase chain reaction. Moreover, legumain (Lgmn) expression was analyzed by immunohistochemistry and quantitative real-time polymerase chain reaction in the cardiac tissues of patients with ischemic cardiomyopathy and healthy control subjects. RESULTS: We identified Lgmn as a gene specifically expressed by cardiac resident macrophages. Lgmn deficiency resulted in a considerable exacerbation in cardiac function, accompanied by the accumulation of apoptotic cardiomyocytes and a reduced index of in vivo efferocytosis in the border area. It also led to decreased cytosolic calcium attributable to defective intracellular calcium mobilization. Furthermore, the formation of LC3-II-dependent phagosome around secondary-encountered apoptotic cardiomyocytes was disabled. In addition, Lgmn deficiency increased infiltration of MHC-IIhigh CCR2+ macrophages and the enhanced recruitment of MHC-IIlow CCR2+ monocytes with downregulation of the anti-inflammatory mediators, interleukin-10, and transforming growth factor-ß and upregulationof the proinflammatory mediators interleukin-1ß, tumor necrosis factor-α, interleukin-6, and interferon-γ. CONCLUSIONS: Our results directly link efferocytosis to wound healing in the heart and identify Lgmn as a significant link between acute inflammation resolution and organ function.

Minimally invasive right infra-axillary thoracotomy for transaortic septal myectomy.

Extended left ventricular septal myectomy remains the gold standard for the treatment of hypertrophic obstructive cardiomyopathy (HOCM) with refractory symptoms. On the basis of traditional modified transaortic Morrow myectomy, we innovatively performed a minimally invasive, video-assisted single-port thoracotomy through the right infra-axillary region. Our procedure can provide good visualization of the left ventricular outflow tract and hypertrophic ventricular septum for accurate resection. It also ensures optimal exposure of the mitral valve in the presence of complex mitral subvalvular structures.

Elevated c-fos expression is correlated with phenotypic switching of human vascular smooth muscle cells derived from lower limb venous varicosities.

BACKGROUND: Lower limb venous varicosities (VVs) are clinically common; however, their molecular underpinnings are far from well elucidated. Previous studies have demonstrated that the phenotypic transition of vascular smooth muscle cells (VSMCs) plays a critical role in VV pathogenesis and that c-fos is upregulated in VSMCs from VVs. The present study investigated the histologic and cytologic changes in VVs and the correlation between c-fos upregulation and VSMC phenotypic switching. METHODS: Thirty-four patients with VVs (VV group) and 13 patients undergoing coronary artery bypass using autologous great saphenous vein segments (normal vein [NV] group) were enrolled in the present study. The great saphenous veins of both groups were harvested for subsequent experiments. Hematoxylin and eosin staining was performed for vein morphologic analysis. Real-time quantitative polymerase chain reaction, immunohistochemistry, and Western blot assays were used to assess mRNA and protein expression of c-fos, α-smooth muscle actin (α-SMA), and osteopontin (OPN). Simple linear regression was used to evaluate the correlation between c-fos and OPN/α-SMA. Primary VSMCs were isolated from both groups and cultured in vitro. A cell counting kit-8 assay and scratch-wound assay were used to analyze the proliferation and migration abilities of the cells, respectively. RESULTS: The mean age of the patients in the NV and VV groups was 61.4 ± 3.8 years and 59.5 ± 10.4 years, respectively. The vein cavities of the VV group were dilated, and the arrangement of the cells was disordered. The tunica media of the VV group was thicker than that of the NV group owing to the accumulation and proliferation of VSMCs. Significantly elevated mRNA levels of c-fos and OPN were observed in the VV group compared with the NV group, and a positive correlation was further demonstrated between the mRNA levels of c-fos and OPN/α-SMA (R2, 0.5524; P < .001). The VSMCs derived from the VV group were more numerous (as shown by the cell counting kit-8 assay) and had a significantly greater migration speed (as shown by the scratch-wound assay) than those derived from the NV group. Moreover, the protein expression of c-fos was significantly upregulated in VSMCs derived from the VV group, and this change was accompanied by a decrease in α-SMA and an increase in OPN expression. CONCLUSIONS: Both mRNA and protein expression of c-fos were upregulated in VV specimens, and the phenotypic biomarkers (OPN/α-SMA) were altered concurrently. VSMCs derived from VVs showed increased proliferation and migration abilities. Upregulation of c-fos might play a role in the phenotypic switching of VSMCs and subsequently participate in the pathogenesis of VVs. CLINICAL RELEVANCE: C-fos is an immediate early gene owing to the transient and rapid change in its expression in response to stimuli. It is involved in the regulation of cell proliferation, cell growth, and cell movement. In the present study, varicose vein specimens showed increased mRNA and protein expression of c-fos, accompanied by altered phenotypic biomarkers. The upregulation of the c-fos gene in smooth muscle cells cultured from varicose vein specimens might be associated with phenotypic switching and functional disturbance. These results could contribute to the exploration of the molecular mechanisms underlying the pathogenesis of varicose veins and the development of new therapeutic strategies.

The Role of Cariporide in Protecting Saphenous Vein among Different Aldehyde Dehydrogenase Genotypes.

OBJECTIVE: We aimed to study the effect of cariporide (CP) on protecting the saphenous vein and the role of acetaldehyde dehydrogenase 2 (ALDH2) in coronary artery bypass grafting (CABG). BACKGROUND: The saphenous vein is the main graft material used in CABG. Recent studies suggested that CP is effective in protecting against various cardiovascular diseases. METHODS: Segments of a surgically removed saphenous vein were used to examine the vascular response to CP. The ALDH2 genotype and expression of related proteins were assessed by Western blotting and immunohistochemistry. RESULTS: Among the conditions tested, the University of Wisconsin solution with CP (4°C, 5 min) treatment showed the best protective effect on the saphenous vein. The incidence of major adverse cardiac events was higher in the ALDH2-GA (heterozygous mutant) genotype population after CABG. CONCLUSION: CP plays a role in reducing the production of reactive oxygen species and apoptosis by ALDH2-mediated mitochondrial function improvement. The ALDH2 mutant genotype might be one of the risk factors for coronary atherosclerotic heart disease.