Early cholesterol spikes fuel atherosclerosis by altering macrophages

Discover how early cholesterol fluctuations disrupt critical immune cells, accelerating heart disease risk and highlighting the urgency for proactive cholesterol management.

Study: Early intermittent hyperlipidaemia alters tissue macrophages to fuel atherosclerosis. Image Credit: crystal light / ShutterstockStudy: Early intermittent hyperlipidaemia alters tissue macrophages to fuel atherosclerosis. Image Credit: crystal light / Shutterstock

In a recent study published in the journal Nature, a group of researchers investigated how early intermittent hyperlipidemia (High blood fat levels) accelerates atherosclerosis (Artery plaque buildup) by altering the number and homeostatic phenotype of resident-like tissue macrophages and identifying the underlying biological mechanisms contributing to increased atherosclerotic cardiovascular disease (ASCVD) risk.

Background 

A wealth of evidence links cholesterol to the development of atherosclerosis, partly through activation of the NLR Family Pyrin Domain Containing 3 - Interleukin 1 Beta (NLRP3-IL1β) pathway.

However, the exact mechanisms driving inflammatory plaque formation in response to cholesterol overload remain unclear. Beyond Low-Density Lipoprotein Cholesterol (LDL-C) levels, the duration of exposure and the area under the LDL-C vs. age curve are strong predictors of ASCVD events.

Notably, early cholesterol accumulation poses a higher CVD risk, and fluctuations in cholesterol levels, even with statin treatment, increase ASCVD risk.

Further research is needed to fully understand the precise mechanisms by which early and intermittent cholesterol variations accelerate atherosclerosis, particularly through the alteration of actin filament organization and macrophage-related pathways, enabling the development of more effective therapeutic strategies for ASCVD prevention.

About the study 

Mice used in the study were on a C57BL/6 (A common inbred strain of laboratory mice) background, including Lysozyme 2-Cre recombinase heterozygous (Lyz2Cre+/−), Low-Density Lipoprotein Receptor knockout (Ldlr−/−), Recombination Activating Gene 2 knockout (Rag2−/−) from Charles River, and Apolipoprotein E knockout (Apoe-/-) from Comparative Medicine. Spicflox/flox mice were provided by researchers from Japan, and Lyz2Cre+/− with Neuropilin 1 floxed (Lyz2Cre+/− Nrp1flox/flox) mice were generated at University College London. Apoe-/-lymphatic vessel endothelial hyaluronic acid receptor 1 Lyve1-Cre)/wt floxed colony-stimulating factor 1 receptor (Csf1r)rflox/flox mice were created through crossbreeding, and some mice were injected with Adeno-Associated Virus serotype 8 encoding mutant Proprotein Convertase Subtilisin/Kexin Type 9 (D377Y variant) (AAV8-D377Y-mPCSK9) virus to induce hypercholesterolemia.

All in vivo experiments using mice were conducted under ethical approval from respective Institutional Review Boards, including the Home Office (United Kingdom), French National Institute of Health and Medical Research (INSERM) Ethical Committee (France), Institutional Animal Care and Use Committee (IACUC) (Singapore), and the United States of America (USA)’s protocol 2111-39587A. 

Mice were housed in pathogen-free facilities, with temperature and humidity controlled. Atherosclerosis experiments typically began at 6 weeks of age, with mice randomly assigned to experimental groups.

Sample sizes were determined to ensure sufficient power to detect significant differences in lesion size. Bone marrow transplants involved irradiating Ldlr−/− mice, followed by reconstitution with sex-matched donor bone marrow cells. Blood was collected to measure plasma cholesterol levels, and tissues were stained for histology and immunohistochemistry analysis of atherosclerotic lesions.

The study also employed RNA sequencing and microbiota analysis to identify gene expression changes and the impact of gut microbiota on atherosclerosis. Ribonucleic Acid (RNA) sequencing and microbiota analysis were also conducted, with gene expression analyzed using RNAseq pipelines and relevant bioinformatics tools.

Study results 

Animal models of atherosclerosis typically rely on inducing hyperlipidemia to study the progression of the disease, with plaque size correlating with cholesterol levels in circulation.

Since the first model was developed, these models have mostly focused on inducing prolonged high cholesterol levels during the latter part of the animals’ lives. However, these models do not account for lifelong variations in cholesterol exposure, which is more reflective of the human experience.

To address this, a new model was developed to introduce early intermittent hyperlipidemia in mice, keeping overall cholesterol exposure (area under the curve) equivalent to traditional late sustained hyperlipidemia models.

In a series of experiments, Ldlr−/− male mice were fed either a late continuous Western diet (cWD) or an early intermittent Western diet (iWD).

Plasma cholesterol levels and other physiological markers such as heart rate, weight, and blood pressure remained similar between the two groups. Despite this, mice subjected to the early intermittent diet had significantly larger atherosclerotic plaques compared to those on the continuous diet.

This result was consistent across both male and female mice, although the magnitude of plaque size increase varied more in females.

The plaques in the iWD mice were not only larger but also showed increased inflammation and necrosis, with plaques in the iWD mice characterized by increased inflammation, with higher numbers of macrophages and T cells and larger necrotic cores, indicating altered plaque healing and increased disease severity.

The study further explored the role of the gut microbiota, which can be affected by the Western diet and potentially influence the development of atherosclerosis.

After six weeks of diet, gut microbiota composition differed slightly between the two groups. However, antibiotic treatment reduced the acceleration of atherosclerosis in iWD-fed mice but did not entirely prevent it, suggesting a limited role for microbiota in this model.

Adaptive immunity was also investigated, with Ldlr−/−/Rag2−/− mice (lacking T and B cells) still showing accelerated atherosclerosis under iWD, suggesting that innate rather than adaptive immune responses are critical in this process.

Further analysis through RNA sequencing revealed significant changes in macrophage gene expression, particularly related to autophagy and efferocytosis, which are essential for plaque stability. These findings were linked to the impaired function of resident-like macrophages, crucial for maintaining arterial health.

Additionally, RNA sequencing revealed that early intermittent hyperlipidemia led to reduced autophagy in macrophages, contributing to the larger, more necrotic plaques observed in these mice.

Conclusions 

This study demonstrates that early intermittent hyperlipidemia is a major driver of atherosclerotic plaque development, even when cumulative cholesterol levels are similar to late hyperlipidemia.

Early-life exposure to high cholesterol significantly influences the progression of atherosclerosis, explaining the strong link between early cholesterol fluctuations and later cardiovascular events.

The study highlights the importance of controlling cholesterol levels early in life to prevent long-term cardiovascular risks. It identifies impaired autophagy and efferocytosis pathways in arterial macrophages, particularly in resident-like macrophages, as key contributors to accelerated atherosclerosis. Early cholesterol control is crucial for reducing long-term cardiovascular risk.

Journal reference:
Vijay Kumar Malesu

Written by

Vijay Kumar Malesu

Vijay holds a Ph.D. in Biotechnology and possesses a deep passion for microbiology. His academic journey has allowed him to delve deeper into understanding the intricate world of microorganisms. Through his research and studies, he has gained expertise in various aspects of microbiology, which includes microbial genetics, microbial physiology, and microbial ecology. Vijay has six years of scientific research experience at renowned research institutes such as the Indian Council for Agricultural Research and KIIT University. He has worked on diverse projects in microbiology, biopolymers, and drug delivery. His contributions to these areas have provided him with a comprehensive understanding of the subject matter and the ability to tackle complex research challenges.    

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