Targeting foam cell formation and macrophage polarization in atherosclerosis: The Therapeutic potential of rhubarb.

Atherosclerosis, a chronic inflammatory disease associated with high morbidity and mortality, is characterized by the accumulation of foam cells in the arterial wall. It has long been acknowledged that the formation of foam cells is caused by excess lipid uptake and abnormal cholesterol metabolism function. And increasing evidence shows that inhibiting foam cell formation is a promising way to suppress the development of atherosclerotic lesions. In addition to excess foam cells accumulation, inflammation is another major contributor of atherosclerotic lesions. Recently, macrophage polarization has been demonstrated to play a vital role in the regulation of inflammatory response. Generally, macrophages mainly polarized into two phenotypes: either classically activated pro-inflammatory M1 or alternatively activated anti-inflammatory M2. And targeting macrophage polarization has been considered as a feasible approach to prevent the development of atherosclerosis. At present, the anti-atherosclerosis drugs mainly classified into two types: lipid-lowering drugs and anti-inflammatory drugs. A large part of those drugs belong to western medicine, and various side effects are unavoidable. Interestingly, in recent years, Traditional Chinese medicine has attracted growing attention because of its good efficacy and low negative effects. Rhubarb (called Da Huang in Chinese) is a famous folk medicine with a wide spectrum of pharmacological effects, such as lipid-lowering and anti-inflammatory effects. In this review, we summarized current findings about the regulatory effects of Rhubarb on foam cell formation and macrophage polarization, with emphasis on the molecular mechanisms of action that have been revealed during the past two decades, to better understand its pivotal role in the treatment and prevention of atherosclerosis.

Liu X ，Wu J ，Tian R ，Su S ，Deng S ，Meng X ... -  《-》

IgE Contributes to Atherosclerosis and Obesity by Affecting Macrophage Polarization, Macrophage Protein Network, and Foam Cell Formation.

Zhang X ，Li J ，Luo S ，Wang M ，Huang Q ，Deng Z ，de Febbo C ，Daoui A ，Liew PX ，Sukhova GK ，Metso J ，Jauhiainen M ，Shi GP ，Guo J ... -  《-》

LongShengZhi Capsule Reduces Established Atherosclerotic Lesions in apoE-Deficient Mice by Ameliorating Hepatic Lipid Metabolism and Inhibiting Inflammation.

Ma J ，Zhao D ，Wang X ，Ma C ，Feng K ，Zhang S ，Chen Y ，Zhu Y ，Gao X ，Zhao B ，Wang Y ，Qian K ，Li X ，Duan Y ，Han J ，Yang X ... -  《-》

Bifunctional supramolecular nanofiber inhibits atherosclerosis by enhancing plaque stability and anti-inflammation in apoE(-/-) mice.

Background and Purpose: Atherosclerosis is vascular disease of chronic inflammation and lipid disorder, which is a major cause of coronary heart disease. Foam cell formation is key progress during the atherosclerosis development. Insulin-like growth factor (IGF)-1 is a growth hormone that plays a crucial role in growth, metabolism, and homeostasis. Previous studies have demonstrated that increase in circulating IGF-1 can reduce atherosclerotic burden. However, active IGF-1 is characterized with poor tissue retention and is at a very low level in circulation system. Therefore, supplementation of exogenous IGF-1 to restore the physiological level is a promising approach to inhibit atherosclerosis. In this study, we develop a self-assembling, anti-inflammatory drug-modified peptide derived from IGF-1 to mimic IGF-1 bioactivity and simultaneously with an anti-inflammatory property for the treatment of atherosclerosis. Methods: ApoE-/- mice were subcutaneously (s.c.) injected with the different hydrogels or natural IGF-1 protein solution per week and simultaneously fed a high-fat diet for 16 weeks. Atherosclerotic lesion formation and stability were assessed after treatment. Moreover, peritoneal macrophage and serum samples were collected to determine lipid profile and inflammatory cytokines. Concurrently, we determined the effect of bifunctional supramolecular nanofibers/hydrogel on cholesterol efflux, foam cell formation, phenotypic transformation of VSMC to macrophage-like cells, and macrophage polarization in vitro or in vivo. Results: Bifunctional supramolecular nanofibers/hydrogel for the treatment of atherosclerosis was formed by a short peptide consisting of a tetrapeptide SSSR from C-region of growth factor IGF-1, an anti-inflammatory drug naproxen (Npx), and a powerful self-assembling D-peptide DFDF. The resulting hydrogel of Npx-DFDFGSSSR (Hydrogel 1, H1) possessed both the anti-inflammatory and IGF-1 mimicking properties, and it efficiently promoted the expression of ABCA1 and ABCG1, thereby significantly reducing cholesterol accumulation in macrophages and preventing foam cell formation. Moreover, H1 markedly inhibited the transformation of vascular smooth muscle cells (VSMCs) into macrophage-like cells which also contributed to foam cell formation. In addition, H1 significantly reduced the inflammatory response in vitro and in vivo. Most importantly, the IGF-1 mimetic peptide showed comparable performance to IGF-1 in vivo and inhibited atherosclerosis by markedly reducing lesion area and enhancing plaque stability. Conclusions: Our study provides a novel supramolecular nanomaterial to inhibit pathological progress of atherosclerosis through regulating cholesterol efflux and inflammation, which may contribute to the development of a promising nanomedicine for the treatment of atherosclerosis in the clinic.

Shang Y ，Ma C ，Zhang J ，Wang Z ，Ren C ，Luo X ，Peng R ，Liu J ，Mao J ，Shi Y ，Fan G ... -  《Theranostics》

Cytokines, macrophage lipid metabolism and foam cells: implications for cardiovascular disease therapy.

Cardiovascular disease is the biggest killer globally and the principal contributing factor to the pathology is atherosclerosis; a chronic, inflammatory disorder characterized by lipid and cholesterol accumulation and the development of fibrotic plaques within the walls of large and medium arteries. Macrophages are fundamental to the immune response directed to the site of inflammation and their normal, protective function is harnessed, detrimentally, in atherosclerosis. Macrophages contribute to plaque development by internalizing native and modified lipoproteins to convert them into cholesterol-rich foam cells. Foam cells not only help to bridge the innate and adaptive immune response to atherosclerosis but also accumulate to create fatty streaks, which help shape the architecture of advanced plaques. Foam cell formation involves the disruption of normal macrophage cholesterol metabolism, which is governed by a homeostatic mechanism that controls the uptake, intracellular metabolism, and efflux of cholesterol. It has emerged over the last 20 years that an array of cytokines, including interferon-γ, transforming growth factor-β1, interleukin-1β, and interleukin-10, are able to manipulate these processes. Foam cell targeting, anti-inflammatory therapies, such as agonists of nuclear receptors and statins, are known to regulate the actions of pro- and anti-atherogenic cytokines indirectly of their primary pharmacological function. A clear understanding of macrophage foam cell biology will hopefully enable novel foam cell targeting therapies to be developed for use in the clinical intervention of atherosclerosis.

McLaren JE ，Michael DR ，Ashlin TG ，Ramji DP ... -  《-》