Hypercholesterolemia is a significant risk factor for the development of atherosclerosis. 2',3',5'-Tri-O-acetyl-N ⁶-(3-hydroxyphenyl) adenosine (IMM-H007), a novel AMPK agonist, has shown protective effects in metabolic diseases. However, its impact on cholesterol and triglyceride metabolism in hypercholesterolemia remains unclear. In this study, we aimed to elucidate the effects and specific mechanisms by which IMM-H007 regulates cholesterol and triglyceride metabolism. To achieve this goal, we used Apoe ^-/- and Ldlr ^-/- mice to establish a hypercholesterolemia/atherosclerosis model. Additionally, hepatocyte-specific Ampka1/2 knockout mice were subjected to a 5-week high-cholesterol diet to establish hypercholesterolemia, while atherosclerosis was induced via AAV-PCSK9 injection combined with a 16-week high-cholesterol diet. Our results demonstrated that IMM-H007 improved cholesterol and triglyceride metabolism in mice with hypercholesterolemia. Mechanistically, IMM-H007 modulated the AMPKα1/2-LDLR signaling pathway, increasing cholesterol uptake in the liver. Furthermore, IMM-H007 activated the AMPKα1-FXR pathway, promoting the conversion of hepatic cholesterol to bile acids. Additionally, IMM-H007 prevented hepatic steatosis by activating the AMPKα1/2-ATGL pathway. In conclusion, our study suggests that IMM-H007 is a promising therapeutic agent for improving hypercholesterolemia and atherosclerosis through the activation of AMPKα.

Aim Krüppel-like factor(KLF)2 and 4 are two core transcription factors closely related to vascular homeostasis,with multiple protective effects such as anti-inflammatory,anti-calcification and anti-thrombotic.The aim of this study is to elucidate and validate the vascular homeostasis related gene profile co-regulated by KLF2 and KLF4 in endo-thelial cells.Methods Human umbilical vein endothelial cells(HUVEC)were treated with adenovirus(Ad-KLF2 or Ad-KLF4)and control virus(Ad-NC)for 24 h,RNA was extracted from the cells and analyzed by transcriptomic sequen-cing.The sequencing results of overexpressed KLF2 and KLF4 were superimposed with the sequencing results of reported KLF2/KLF4 double-gene knockout mice.The selected differential expression genes were verified by real-time fluorescence quantitative PCR in HUVEC treated with Ad-KLF2 or Ad-KLF4,and in HUVEC treated with atorvastatin or resveratrol.Results Transcriptomic superposition revealed 256 differential expression genes were up-regulated by KLF2 and KLF4,and KEGG analysis showed that differential expression genes were enriched in hypertrophic cardiomyopa-thy,arrhythmogenic right ventricular cardiomyopathy,dilated cardiomyopathy,ECM-receptor interaction and focal adhesion;there were 145 differential expression genes down-regulated by KLF2 and KLF4,and KEGG analysis showed that differential expression genes were enriched in microRNA of cancer,mineral absorption,glycosaminoglycan biosynthesis-chondroitin sulfate/dermatan sulfate,p53 signaling pathway and biosynthesis of amino acids.Finally,six novel genes regulated by KLF2 and KLF4 were obtained.Conclusion FGFR3,SEMA4B,SEMA6A,PTX3,FABP4 and FABP5 may be novel genes that regulate vascular homeostasis in endothelial cells by the transcription factors KLF2 and KLF4.

Bioactive compounds derived from herbal medicinal plants modulate various therapeutic targets and signaling pathways associated with cardiovascular diseases (CVDs), the world's primary cause of death. Ginkgo biloba, a well-known traditional Chinese medicine with notable cardiovascular actions, has been used as a cardio- and cerebrovascular therapeutic drug and nutraceutical in Asian countries for centuries. Preclinical studies have shown that ginkgolide B, a bioactive component in Ginkgo biloba, can ameliorate atherosclerosis in cultured vascular cells and disease models. Of clinical relevance, several clinical trials are ongoing or being completed to examine the efficacy and safety of ginkgolide B-related drug preparations in the prevention of cerebrovascular diseases, such as ischemia stroke. Here, we present a comprehensive review of the pharmacological activities, pharmacokinetic characteristics, and mechanisms of action of ginkgolide B in atherosclerosis prevention and therapy. We highlight new molecular targets of ginkgolide B, including nicotinamide adenine dinucleotide phosphate oxidases (NADPH oxidase), lectin-like oxidized LDL receptor-1 (LOX-1), sirtuin 1 (SIRT1), platelet-activating factor (PAF), proprotein convertase subtilisin/kexin type 9 (PCSK9) and others. Finally, we provide an overview and discussion of the therapeutic potential of ginkgolide B and highlight the future perspective of developing ginkgolide B as an effective therapeutic agent for treating atherosclerosis.

Peroxisome proliferator-activated receptor (PPAR) is a transcriptional coactivator that binds to a diverse range of transcription factors. PPAR coactivator 1 (PGC-1) coactivators possess an extensive range of biological effects in different tissues, and play a key part in the regulation of the oxidative metabolism, consequently modulating the production of reactive oxygen species, autophagy, and mitochondrial biogenesis. Owing to these findings, a large body of studies, aiming to establish the role of PGC-1 in the neuromuscular system, has shown that PGC-1 could be a promising target for therapies targeting neuromuscular diseases. Among these, some evidence has shown that various signaling pathways linked to PGC-1 are deregulated in muscular dystrophy, leading to a reduced capacity for mitochondrial oxidative phosphorylation and increased reactive oxygen species (ROS) production. In the light of these results, any intervention aimed at activating PGC-1 could contribute towards ameliorating the progression of muscular dystrophies. PGC-1 is influenced by different patho-physiological/pharmacological stimuli. Natural products have been reported to display modulatory effects on PPAR activation with fewer side effects in comparison to synthetic drugs. Taken together, this review summarizes the current knowledge on Duchenne muscular dystrophy, focusing on the potential effects of natural compounds, acting as regulators of PGC-1.

Inflammation plays a pivotal role in atherogenesis. In addition to being a potent predictive and prognostic marker for major cardiovascular events, recent evidence indicates that C-reactive protein (CRP) might directly promote atherogenesis by exerting direct effects on vascular cells. Thus, CRP will become important novel pharmaceutical targets for the treatment of atherosclerosis. This review presents an overview of the current knowledge about the pathological role of CRP in atherosclerosis initiation and progression.