Atherosclerosis is a smooth muscle cell-driven tumor-like disease

Abstract

Atherosclerosis, the leading cause of cardiovascular disease, is a chronic inflammatory disease involving pathological activation of multiple cell types, such as immunocytes (e.g., macrophage, T cells), smooth muscle cells (SMCs), and endothelial cells. Multiple lines of evidence have suggested that SMC "phenotypic switching" plays a central role in atherosclerosis development and complications. Yet, SMC roles and mechanisms underlying the disease pathogenesis are poorly understood. Here, employing SMC lineage tracing mice, comprehensive molecular, cellular, histological, and computational profiling, coupled to genetic and pharmacological studies, we reveal that atherosclerosis, in terms of SMC behaviors, share extensive commonalities with tumors. SMC-derived cells in the disease show multiple characteristics of tumor cell biology, including genomic instability, replicative immortality, malignant proliferation, resistance to cell death, invasiveness, and activation of comprehensive cancer-associated gene regulatory networks. SMC-specific expression of oncogenic KrasG12D accelerates SMC phenotypic switching and exacerbates atherosclerosis. Moreover, we present a proof of concept showing that niraparib, an anti-cancer drug targeting DNA damage repair, attenuates atherosclerosis progression and induces regression of lesions in advanced disease in mouse models. Our work provides systematic evidence that atherosclerosis is a tumor-like disease, deepening the understanding of its pathogenesis and opening prospects for novel precision molecular strategies to prevent and treat atherosclerotic cardiovascular disease.

A Concept of “Athero-Oncology”: Tumor-Like Smooth Muscle Cells Drive Atherosclerosis

“…Kras variants have not been directly associated with atherosclerotic lesions; however, this study detected gain-of-copy copy number variations in the Kras locus in human plaques. 1 This study 1 suggests that DNA damage, a hallmark of aging, is an important driver of atherosclerosis, but notably highlights the necessary interplay between DNA damage and a hyperlipidemic environment in atherosclerosis models. Substantial SMC/SDC DNA damage was detected in aged mice on a Western diet, but not on a chow diet.…”

“…This study 1 suggests that DNA damage, a hallmark of aging, is an important driver of atherosclerosis, but notably highlights the necessary interplay between DNA damage and a hyperlipidemic environment in atherosclerosis models. Substantial SMC/SDC DNA damage was detected in aged mice on a Western diet, but not on a chow diet.…”

“…In this issue, new work by Pan et al 1 suggests a novel “athero-oncology” paradigm that SDCs in atherosclerotic plaques exhibit many similarities to cancer cells. Using fate mapping methods, the authors found that oxidative DNA damage and genomic instability accumulate in SMCs and SDCs in mouse and human atherosclerotic lesions.…”

“…Kras variants have not been directly associated with atherosclerotic lesions; however, this study detected gain-of-copy copy number variations in the Kras locus in human plaques. 1…”

“…A study in this issue of Circulation reveals additional intriguing commonalities between tumor cells and smooth muscle cells (SMCs) in the pathogenesis of atherosclerosis. 1…”