Inhibition of macrophage proliferation dominates plaque regression in response to cholesterol lowering.
Carmen HärdtnerJan KornemannKatja KrebsCarolin A EhlertAlina JanderJiadai ZouChristopher StarzSimon RauterbergDiana SharipovaBianca DufnerNatalie HoppeTsai-Sang DederichsFlorian WilleckePeter StachonTimo HeidtDennis WolfConstantin von Zur MühlenJosef MadlPeter KohlRafael KaeserTobias BoettlerElsbeth J PietermanHans M G PrincenBenoît Ho-Tin-NoéFilip K SwirskiClinton S RobbinsChristoph BodeAndreas ZirlikIngo HilgendorfPublished in: Basic research in cardiology (2020)
Statins induce plaque regression characterized by reduced macrophage content in humans, but the underlying mechanisms remain speculative. Studying the translational APOE*3-Leiden.CETP mouse model with a humanized lipoprotein metabolism, we find that systemic cholesterol lowering by oral atorvastatin or dietary restriction inhibits monocyte infiltration, and reverses macrophage accumulation in atherosclerotic plaques. Contrary to current believes, none of (1) reduced monocyte influx (studied by cell fate mapping in thorax-shielded irradiation bone marrow chimeras), (2) enhanced macrophage egress (studied by fluorescent bead labeling and transfer), or (3) atorvastatin accumulation in murine or human plaque (assessed by mass spectrometry) could adequately account for the observed loss in macrophage content in plaques that undergo phenotypic regression. Instead, suppression of local proliferation of macrophages dominates phenotypic plaque regression in response to cholesterol lowering: the lower the levels of serum LDL-cholesterol and lipid contents in murine aortic and human carotid artery plaques, the lower the rates of in situ macrophage proliferation. Our study identifies macrophage proliferation as the predominant turnover determinant and an attractive target for inducing plaque regression.
Keyphrases
- adipose tissue
- low density lipoprotein
- endothelial cells
- coronary artery disease
- signaling pathway
- bone marrow
- mass spectrometry
- mouse model
- cardiovascular disease
- cell fate
- high resolution
- mesenchymal stem cells
- type diabetes
- genome wide
- insulin resistance
- quantum dots
- liquid chromatography
- aortic valve
- immune response
- bone mineral density
- left ventricular
- coronary artery
- dna methylation
- living cells
- tandem mass spectrometry
- simultaneous determination
- atrial fibrillation
- pulmonary hypertension
- high density