Atherosclerosis Is a Smooth Muscle Cell-Driven Tumor-Like Disease.

Area of Science:

• Cardiovascular Biology
• Cancer Biology
• Translational Medicine

Background:

• Atherosclerosis is a major cause of cardiovascular disease, driven by the pathological activation of multiple cell types.
• Smooth muscle cell (SMC) phenotypic switching is increasingly recognized as a critical factor in atherosclerosis development and complications.
• The precise nature and underlying mechanisms of SMC-derived cells in disease pathogenesis are not well understood.

Purpose of the Study:

• To characterize the tumor cell-like behaviors of SMC-derived cells in atherosclerosis.
• To elucidate the mechanisms driving SMC transition in the context of atherosclerosis.
• To explore novel therapeutic strategies targeting SMC transition for atherosclerosis prevention and treatment.

Main Methods:

• Utilized SMC lineage tracing in mice and analysis of human tissues.
• Employed a multidisciplinary approach including molecular, cellular, histological, computational, and genetic methods.
• Investigated the impact of oncogenic Kras expression and tested the efficacy of the anticancer drug niraparib.

Main Results:

• SMC-derived cells in atherosclerosis display tumor cell-like traits: genomic instability, evasion of senescence, hyperproliferation, invasiveness, and cancer-associated gene networks.
• Expression of oncogenic KrasG12D in SMCs accelerates SMC transition and worsens atherosclerosis.
• The DNA damage repair inhibitor niraparib reduced atherosclerosis progression and induced lesion regression in mouse models.

Conclusions:

• Atherosclerosis can be viewed as an SMC-driven, tumor-like disease, offering new insights into its pathogenesis.
• These findings pave the way for innovative precision molecular strategies targeting SMC transition.
• Targeting SMC transition presents a promising therapeutic avenue for atherosclerotic cardiovascular disease.