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The comprehensive study conducted by Chi et al. delved into the role of Nrg4, a secreted protein predominantly found in brown adipose tissue (BAT), in the pathogenesis of atherosclerosis. Utilizing various experimental approaches, they uncovered several pivotal findings that contributed to a better understanding of the protective effects of Nrg4 on endothelial function and atherosclerosis.

To begin, the authors conducted a loss-of-function study in Apoe-/- mice, which were prone to atherosclerosis. They found that Nrg4 deficiency accelerated the formation of atherosclerotic lesions in these mice. Additionally, the deletion of Nrg4 specifically in BAT exacerbated the endothelial injury and atherosclerosis in Apoe-/- mice. These findings suggested that BAT-derived Nrg4 played a crucial role in modulating the development of atherosclerosis.

To further investigate the impact of Nrg4 on atherosclerosis, the authors performed gain-of-function experiments by overexpressing Nrg4 in BAT using adeno-associated virus (AAV) vectors. They discovered that Nrg4 overexpression in BAT reduced endothelial inflammation, leukocyte homing, and macrophage accumulation in atherosclerotic lesions, ultimately attenuating atherosclerosis in Apoe-/- mice.

Graphical abstract. Schematic showing that Nrg4 plays a protective role in atherosclerosis via ErbB4–Akt–NF-κB signaling pathway.

This work describes that BAT-derived Nrg4 serves as a potential cross-talk factor between BAT and arteries and attenuates endothelial inflammation or adhesion responses, inhibits leukocyte homing and reduces endothelial injury or atherosclerosis in a manner involving Akt–NF-κB signaling. Thus, BAT-derived Nrg4 may become a new therapeutic drug for atherosclerosis and BAT could serve as a new target for atherosclerosis.

Credit:doi: 10.1038/s42255-022-00671-0.

The molecular mechanism underlying the protective effects of Nrg4 on endothelial function and atherosclerosis was further elucidated through a series of experiments. The authors demonstrated that Nrg4 inhibited endothelial inflammation and leukocyte homing by suppressing NF-κB signaling through the ErbB4 receptor. Akt was identified as a pivotal downstream mediator of ErbB4 in this signaling pathway. These findings provided a molecular understanding of how Nrg4 exerted its protective effects on endothelial cells and atherosclerotic plaques.

Furthermore, the authors explored the potential translational implications of their findings. They demonstrated that Nrg4 alleviated endothelial dysfunction and atherosclerosis in a human ex vivo model using human mesenteric artery rings. This finding suggested that the beneficial effects of Nrg4 on endothelium and atherosclerosis observed in mice might also be applicable to humans.

In summary, this study revealed that BAT-derived Nrg4 played a crucial role in inhibiting endothelial inflammation and leukocyte homing, thereby maintaining endothelial integrity and plaque stability. The molecular mechanism underlying these effects involved the inhibition of NF-κB signaling through the ErbB4-Akt pathway. This research highlighted the potential of targeting Nrg4 as a novel therapeutic strategy for atherosclerosis.

Similarly, another article, published in Nature Communications, explored the role of perivascular adipose tissue (PVAT) in regulating vascular inflammation and remodeling after injury. The authors used a combination of animal models and human tissue samples to investigate the phenomenon of "beiging" of PVAT after vascular injury and its effects on inflammation and macrophage activation.

In the animal model, endovascular injury was induced in mouse femoral arteries by wire insertion, leading to the infiltration of macrophages into the PVAT surrounding the injured vessels. This infiltration was observed as early as 3 days after injury. The authors then detected upregulation of brown adipose tissue (BAT) markers such as Ucp1, Cidea, and Cox8b in the PVAT, indicating a transition to a BAT-like phenotype or "beiging" of the adipose tissue. This beiging was dependent on macrophage infiltration, as depletion of macrophages with clodronate liposomes abolished the upregulation of BAT markers.

To further investigate the role of PVAT beiging, the authors used mice with adipocyte-specific deletion of the Prdm16 gene, a key regulator of beiging, and found that inhibition of PVAT beiging exacerbated inflammation and vascular remodeling after injury. Conversely, activation of PVAT beiging using a β3-adrenergic receptor agonist attenuated inflammation and vascular remodeling.

The authors used single-cell RNA sequencing to identify neuregulin 4 (Nrg4) as a highly expressed secretory factor in beige adipocytes. They found that Nrg4 was upregulated in PVAT after injury and was critical for the anti-inflammatory effects of PVAT-derived beige adipocytes on macrophages. Knockdown of Nrg4 abolished the inhibitory effects of PVAT-derived beige adipocytes on the growth of classically activated macrophages and the shift to an alternatively activated phenotype.

In human studies, the authors examined PVAT from patients with acute aortic dissection and found increased expression of UCP1, CIDEA, and NRG4, indicating beiging of PVAT in human aortic dissection. Additionally, administration of a β3-adrenergic agonist reduced aortic dissection and mortality in a mouse model of the disease.

In conclusion, the authors' findings demonstrated that vascular injury induced beiging of PVAT, which served as a protective mechanism by fine-tuning the inflammatory response and facilitating the resolution of inflammation. Specifically, PVAT-derived beige adipocytes secreted Nrg4, which inhibited the growth of pro-inflammatory macrophages and promoted their shift to an anti-inflammatory phenotype. This study highlighted the pivotal roles of PVAT beiging and Nrg4 in vascular inflammation and remodeling and suggested they may be novel targets for treating cardiovascular diseases such as atherosclerosis and aortic dissection.

By synthesizing these two literatures, it can be observed that both explore the role of brown or beige fat tissue in cardiovascular health, particularly in its relationship with atherosclerosis. Both literatures emphasize the importance of Nrg4, one in brown fat tissue and the other in the beiging process of perivascular adipose tissue. These studies provide a new perspective on how adipose tissue affects cardiovascular diseases and may offer new targets for future treatment strategies.

Reference:

1. Shi L, Li Y, Xu X, Cheng Y, Meng B, Xu J, Xiang L, Zhang J, He K, Tong J, Zhang J, Xiang L, Xiang G. Brown adipose tissue-derived Nrg4 alleviates endothelial inflammation and atherosclerosis in male mice. Nat Metab. 2022 Nov;4(11):1573-1590.

2. Adachi Y, Ueda K, Nomura S, Ito K, Katoh M, Katagiri M, Yamada S, Hashimoto M, Zhai B, Numata G, Otani A, Hinata M, Hiraike Y, Waki H, Takeda N, Morita H, Ushiku T, Yamauchi T, Takimoto E, Komuro I. Beiging of perivascular adipose tissue regulates its inflammation and vascular remodeling. Nat Commun. 2022 Sep 7;13(1):5117.