Experimental evidence on colchicine's mode of action in human carotid artery plaques
Alexander von Ehr1, Ines Derya Steenbuck2, Charlotte Häfele1
1Department of Cardiology and Angiology, University Heart Center Freiburg-Bad Krozingen, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
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.
Insights
Colchicine impacts atherosclerosis by reducing neutrophil and platelet activation and macrophage proliferation in human plaques. Its anti-inflammatory effects extend beyond the inflammasome, offering potential cardiovascular benefits.
Area of Science:
- Cardiovascular Medicine
- Inflammation Research
- Pharmacology
Background:
- Atherosclerosis is a major cause of cardiovascular events, driven by inflammation.
- Anti-inflammatory treatments show therapeutic promise.
- Colchicine is recommended for secondary prevention, but its mechanisms are unclear.
Purpose of the Study:
- To investigate colchicine's multiomic effects on human carotid plaques.
- To elucidate the mechanistic actions of colchicine in atherosclerosis.
Main Methods:
- Multiomic analysis (RNA sequencing, mass spectrometry) of human carotid plaques treated ex vivo with colchicine.
- Assessment of gene expression, proteomic changes, and in situ cell proliferation.
Main Results:
- Colchicine dose-dependently suppressed neutrophil/platelet degranulation and activation, collagen degradation, and macrophage proliferation.
- Myofibroblast activation was stimulated by colchicine.
- Interleukin-1beta release was not reduced, suggesting the inflammasome is not the primary target.
Conclusions:
- Colchicine acts through multifactorial pathways in human atherosclerotic lesions, beyond the inflammasome.
- Targeting specific pathways like neutrophil/platelet degranulation and macrophage proliferation may offer therapeutic benefits.
- These targeted actions could provide benefits for atherosclerotic cardiovascular disease without colchicine's side effects.
