3,4-dimethoxychalcone induces autophagy and reduces neointimal hyperplasia and aortic lesions in mouse models of atherosclerosis.
Giulia CerratoCarlota Alvarez-LucenaAllan SauvatYanhua HuSabrina ForveilleGuo ChenSylvère DurandFanny AprahamianMarion LeducOmar MotiñoLisardo BoscáQingbo XuOliver KeppGuido KroemerPublished in: Cell death & disease (2023)
Autophagy inducers can prevent cardiovascular aging and age-associated diseases including atherosclerosis. Therefore, we hypothesized that autophagy-inducing compounds that act on atherosclerosis-relevant cells might have a protective role in the development of atherosclerosis. Here we identified 3,4-dimethoxychalcone (3,4-DC) as an inducer of autophagy in several cell lines from endothelial, myocardial and myeloid/macrophagic origin, as demonstrated by the aggregation of the autophagosome marker GFP-LC3 in the cytoplasm of cells, as well as the downregulation of its nuclear pool indicative of autophagic flux. In this respect, 3,4-DC showed a broader autophagy-inducing activity than another chalcone (4,4- dimethoxychalcone), spermidine and triethylene tetramine. Thus, we characterized the potential antiatherogenic activity of 3,4-DC in two different mouse models, namely, (i) neointima formation with smooth muscle expansion of vein segments grafted to the carotid artery and (ii) genetically predisposed ApoE -/- mice fed an atherogenic diet. In the vein graft model, local application of 3,4-DC was able to maintain the lumen of vessels and to reduce neointima lesions. In the diet-induced model, intraperitoneal injections of 3,4-DC significantly reduced the number of atherosclerotic lesions in the aorta. In conclusion, 3,4-DC stands out as an autophagy inducer with potent antiatherogenic activity.
Keyphrases
- cell death
- endoplasmic reticulum stress
- smooth muscle
- induced apoptosis
- dendritic cells
- signaling pathway
- cell cycle arrest
- oxidative stress
- cardiovascular disease
- mouse model
- aortic valve
- physical activity
- pulmonary artery
- risk assessment
- coronary artery
- immune response
- endothelial cells
- pi k akt
- type diabetes
- heart failure
- bone marrow
- mass spectrometry
- cognitive decline
- metabolic syndrome
- weight loss
- mild cognitive impairment
- ultrasound guided
- atrial fibrillation
- pulmonary hypertension
- pulmonary arterial hypertension
- vascular smooth muscle cells
- human health