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Intercellular transfer of SerpinE2 activates PI3K-AKT and β-catenin signaling to promote cardiac hypertrophy

Lifang Lv, Xiao Liu, Xiaona Wang, Huizhen Zhang, Mingxiu Zhang, Chao Li, Yao Liu, Lan Zheng, Ruonan Yang, Guozhao Wei, Lina Xuan, Qiang Gao, Xiaoqiang E, Tong Yu, Tianyu Li, Hongli Shan, Xuelian Li

2025, 5(3): 180-192. doi: 10.1515/fzm-2025-0021

Keywords: cold exposure, serpinE2, cardiac hypertrophy, cellular communication, endocytosis

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Background Effective inhibition of pathological cardiac hypertrophy is critical for managing various cardiovascular diseases, especially in cold environments. The communication between cardiomyocytes and fibroblasts, mediated by secreted proteins, plays a significant role in the development and progression of pathological cardiac hypertrophy. Serpin Family E Member 2 (serpinE2), secreted by fibroblasts into the extracellular space, has been implicated in this process. However, whether serpinE2 can be internalized by cardiomyocytes and whether cold exposure influences this process remains unclear. Materials and methods Mice were subjected to cold exposure (4 ℃, 12 h/day for 8 weeks), and cardiac hypertrophy was induced by transverse aortic constriction (TAC). SerpinE2 expression was silenced by short interfering RNA (siRNA). Cardiac fibroblasts were stimulated with angiotensin Ⅱ (Ang Ⅱ) to induce serpinE2 secretion. Exogenous recombinant serpinE2, labeled with DyLight 488 or His-tag, was used to evaluate its internalization and functional role in cardiomyocytes. Internalization was inhibited by using antibodies against serpinE2, heparin, or endocytosis inhibitors (β-cyclodextrin, nystatin, dynasore, and chlorpromazine). Chromatin immunoprecipitation followed by quantitative polymerase chain reaction (PCR) was used to assess the binding of the transcription factor CDX1 to the serpinE2 promoter. Results Cold exposure significantly increased serpinE2 mRNA and protein expression in mouse hearts. SerpinE2 levels were also upregulated in plasma and cardiac tissue following TAC. Knockdown of serpinE2 attenuated TAC-induced hypertrophy, restored left ventricular function, and reduced atrial natriuretic peptide, brain natriuretic peptide, and β-myosin heavy chain fragment levels. Exogenous serpinE2 promoted cardiomyocyte hypertrophy, an effect that was reversed by serpinE2 knockdown. Co-culture with conditioned medium from Ang Ⅱ-stimulated fibroblasts increased serpinE2 expression in cardiomyocytes. Exogenous serpinE2 was internalized via endocytosis, which was inhibited by antibodies, heparin, and endocytosis blockers. Internalized serpinE2 activated the protein kinase B (AKT)/β-catenin pathway in cardiomyocytes. CDX1 bound to the serpinE2 promoter and promoted its transcription in fibroblasts. CDX1 overexpression increased serpinE2 and collagen expression, while its suppression had the opposite effect. Administration of exogenous fibroblast growth factor 4 (FGF4) or overexpression of FGF4 plasmid upregulated CDX1, serpinE2, and collagen expression in fibroblasts. Conclusions SerpinE2 expression is responsive to cold stress and mediates intercellular communication between fibroblasts and cardiomyocytes. Fibroblast-secreted serpinE2 is internalized by cardiomyocytes via endocytosis, promoting hypertrophy through activation of the phosphatidylinositol 3-kinase (PI3K)-AKT/β-catenin pathway. The FGF4-CDX1 axis regulates serpinE2 expression and secretion in cardiac fibroblasts.

Ethanol extract of cassia seed alleviates metabolic dysfunction-associated steatotic liver disease by acting on multiple lipid metabolism-related pathways

Wen Li, Jia Wang, Yilian Yang, Chunlei Duan, Bing Shao, Mingxiu Zhang, Jiapan Wang, Peifeng Li, Ye Yuan, Yan Zhang, Hongyu Ji, Xingda Li, Zhimin Du

2024, 4(3): 160-176. doi: 10.1515/fzm-2024-0017

Keywords: cassia seed ethanol extract, metabolic dysfunction related fatty liver disease, network pharmacology

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Background and objective In northern China's cold regions, the prevalence of metabolic dysfunction-associated steatotic liver disease (MASLD) exceeds 50%, significantly higher than the national and global rates. MASLD is an important risk factor for cardiovascular and cerebrovascular diseases, including coronary heart disease, stroke, and tumors, with no specific therapeutic drugs currently available. The ethanol extract of cassia seed (CSEE) has shown promise in lowering blood lipids and improving hepatic steatosis, but its mechanism in treating MASLD remains underexplored. This study aims to investigate the therapeutic effects and mechanisms of CSEE. Methods MASLD models were established in male Wistar rats and golden hamsters using a high fat diet (HFD). CSEE (10, 50, 250 mg/kg) was administered via gavage for six weeks. Serum levels of total cholesterol (TC), triglyceride (TG), lowdensity lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), aspartate aminotransferase (AST), and alanine aminotransferase (ALT), as well as liver TC and TG, were measured using biochemical kits. Histopathological changes in the liver were evaluated using Oil Red O staining, Hematoxylin-eosin (H&E) staining, and transmission electron microscopy (TEM). HepG2 cell viability was assessed using the cell counting kit-8 (CCK8) and Calcein-AM/PI staining. Network pharmacology was used to analyze drug-disease targets, and western blotting was used to confirm these predictions. Results CSEE treatment significantly reduced serum levels of TC, TG, LDL-C, ALT, and AST, and improved liver weight, liver index, and hepatic lipid deposition in rats and golden hamsters. In addition, CSEE alleviated free fatty acid (FFA)-induced lipid deposition in HepG2 cells. Molecular biology experiments demonstrated that CSEE increased the protein levels of p-AMPK, p-ACC, PPARα, CPT1A, PI3K P110 and p-AKT, while decreasing the protein levels of SREBP1, FASN, C/EBPα, and PPARγ, thus improving hepatic lipid metabolism and reducing lipid deposition. The beneficial effects of CSEE were reversed by small molecule inhibitors of the signaling pathways in vitro. Conclusion CSEE improves liver lipid metabolism and reduces lipid droplet deposition in Wistar rats and golden hamsters with MASLD by activating hepatic AMPK, PPARα, and PI3K/AKT signaling pathways.

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