Atherosclerosis · 2025
Experimental evidence on colchicine's mode of action in human carotid artery plaques.
СтатьяПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод пока не подготовлен
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von Ehr Alexander, Steenbuck Ines Derya, Häfele Charlotte, Remmersmann Felix, Vico Tamara A, Ehlert Carolin, Lindner Diana, Wolf Dennis, Tholen Stefan, Schilling Oliver, Czerny Martin, Westermann Dirk, Hilgendorf Ingo
Аннотация
BACKGROUND AND AIMS: Atherosclerosis, driven by inflammation, is a leading cause of cardiovascular events. Recent clinical trials have highlighted the therapeutic potential of anti-inflammatory treatments. Consequently, colchicine is being recommended for secondary prevention in current guidelines, although the drug's mechanistic actions are not fully understood.
METHODS: To this end, we conducted a multiomic investigation of colchicine's effect on human carotid plaques. Sections from endarterectomy specimens were exposed to colchicine at concentrations of 2 ng/ml and 10 ng/ml ex vivo for 24 h and compared to untreated segments of the same plaque. Gene expression changes were analyzed by bulk RNA sequencing, and plaque secretomes underwent mass spectrometry for proteomic analysis. In situ cell proliferation was assessed by histology.
RESULTS: Our data indicate, that colchicine suppresses neutrophil and platelet degranulation and activation, collagen degradation and atheromatous plaque macrophage proliferation in a dose-dependent manner in human plaques, while stimulating myofibroblast activation. Unexpectedly, interleukine (IL)-1beta release from colchicine treated plaques was not reduced. These results indicate that the inflammasome may not be the predominant target of low-dose colchicine in human carotid artery plaques.
CONCLUSION: Our study identifies multifactorial pathways through which colchicine, the first cardiovascular guideline-recommended anti-inflammatory drug, predominantly acts on human atherosclerotic lesions beyond the inflammasome. Targeting neutrophil and platelet degranulation, collagen degradation and macrophage proliferation, selectively, may provide substantial therapeutic benefit in atherosclerotic cardiovascular disease without colchicine's undesired side effects.
METHODS: To this end, we conducted a multiomic investigation of colchicine's effect on human carotid plaques. Sections from endarterectomy specimens were exposed to colchicine at concentrations of 2 ng/ml and 10 ng/ml ex vivo for 24 h and compared to untreated segments of the same plaque. Gene expression changes were analyzed by bulk RNA sequencing, and plaque secretomes underwent mass spectrometry for proteomic analysis. In situ cell proliferation was assessed by histology.
RESULTS: Our data indicate, that colchicine suppresses neutrophil and platelet degranulation and activation, collagen degradation and atheromatous plaque macrophage proliferation in a dose-dependent manner in human plaques, while stimulating myofibroblast activation. Unexpectedly, interleukine (IL)-1beta release from colchicine treated plaques was not reduced. These results indicate that the inflammasome may not be the predominant target of low-dose colchicine in human carotid artery plaques.
CONCLUSION: Our study identifies multifactorial pathways through which colchicine, the first cardiovascular guideline-recommended anti-inflammatory drug, predominantly acts on human atherosclerotic lesions beyond the inflammasome. Targeting neutrophil and platelet degranulation, collagen degradation and macrophage proliferation, selectively, may provide substantial therapeutic benefit in atherosclerotic cardiovascular disease without colchicine's undesired side effects.