Macrophage KLF15 prevents foam cell formation and atherosclerosis via transcriptional suppression of OLR-1.

BACKGROUND: Macrophage-derived foam cells are a hallmark of atherosclerosis. Scavenger receptors, including lectin-like oxidized low-density lipoprotein (LDL) receptor-1 (OLR-1), are the principal receptors responsible for the uptake and modification of LDL, facilitating macrophage lipid load and the uptake of oxidized LDL by arterial wall cells. Krüppel-like factor 15 (KLF15) is a transcription factor that regulates the expression of genes by binding to the promoter during transcription. Therefore, this study aimed to investigate the precise role of macrophage KLF15 in atherogenesis. METHODS: We used two murine models of atherosclerosis: mice injected with an adeno-associated virus (AAV) encoding the Asp374-to-Tyr mutant version of human PCSK9, followed by 12 weeks on a high-fat diet (HFD), and ApoE-/-- mice on a HFD. We subsequently injected mice with AAV-KLF15 and AAV-LacZ to assess the role of KLF15 in the development of atherosclerosis in vivo. Oil Red O, H&E, and Masson's trichome staining were used to evaluate atherosclerotic lesions. Western blots and RT-qPCR were used to assess protein and mRNA levels, respectively. RESULTS: We determined that KLF15 expression was downregulated during atherosclerosis formation, and KLF15 overexpression prevented atherosclerosis progression. KLF15 expression levels did not affect body weight or serum lipid levels in mice. However, KLF15 overexpression in macrophages prevented foam cell formation by reducing OLR-1-meditated lipid uptake. KLF15 directly targeted and transcriptionally downregulated OLR-1 levels. Restoration of OLR-1 reversed the beneficial effects of KLF15 in atherosclerosis. CONCLUSION: Macrophage KLF15 transcriptionally downregulated OLR-1 expression to reduce lipid uptake, thereby preventing foam cell formation and atherosclerosis. Thus, our results suggest that KLF15 is a potential therapeutic target for atherosclerosis.

Macrophage polarization states in atherosclerosis.

Atherosclerosis, a chronic inflammatory condition primarily affecting large and medium arteries, is the main cause of cardiovascular diseases. Macrophages are key mediators of inflammatory responses. They are involved in all stages of atherosclerosis development and progression, from plaque formation to transition into vulnerable plaques, and are considered important therapeutic targets. Increasing evidence suggests that the modulation of macrophage polarization can effectively control the progression of atherosclerosis. Herein, we explore the role of macrophage polarization in the progression of atherosclerosis and summarize emerging therapies for the regulation of macrophage polarization. Thus, the aim is to inspire new avenues of research in disease mechanisms and clinical prevention and treatment of atherosclerosis.

Protective Effects of MicroRNA-200b-3p Encapsulated by Mesenchymal Stem Cells-Secreted Extracellular Vesicles in Myocardial Infarction Via Regulating BCL2L11.

Background Extracellular vesicles (EVs) are a popular treatment candidate for myocardial injury. This work investigated the effects of mesenchymal stem cells (MSCs)-secreted EVs-derived miR-200b-3p on cardiomyocyte apoptosis and inflammatory response after myocardial infarction (MI) through targeting BCL2L11 (Bcl-2-like protein 11) . Methods and Results EVs from MSCs were isolated and identified. EVs from MSCs with transfection of miR-200b-3p for overexpression were injected into MI mice. The effect of miR-200b-3p on cardiac function, infarction area, myocardial fibrosis, cardiomyocyte apoptosis, and inflammatory response was determined in MI mice. The targeting relationship between miR-200b-3p and BCL2L11 was verified, and the interaction between BCL2L11 and NLR family pyrin domain containing 1 (NLRP1) was also verified. MI mice were injected with an overexpressing BCL2L11 lentiviral vector to clarify whether BCL2L11 can regulate the effect of miR-200b-3p on MI mice. EVs from MSCs were successfully extracted. MSCs-EVs improved cardiac function and reduced infarction area, apoptosis of cardiomyocytes, myocardial fibrosis, and inflammation in MI mice. Upregulation of miR-200b-3p further enhanced the effects of MSCs-EVs on the myocardial injury of MI mice. BCL2L11 was targeted by miR-200b-3p and bound to NLRP1. Upregulation of BCL2L11 negated the role of miR-200b-3p-modified MSCs-EVs in MI mice. Conclusions A summary was obtained that miR-200b-3p-encapsulated MSCs-EVs protect against MI-induced apoptosis of cardiomyocytes and inflammation via suppressing BCL2L11.