Biphasic pattern of cell turnover characterizes the progression from fatty streaks to ruptured human atherosclerotic plaques

Esther Lutgens, Ebo D. De Muinck, Peter J.E.H.M. Kitslaar, Jan H.M. Tordoir, Hein J.J. Wellens, Mat J.A.P. Daemen

Research output: Contribution to journalArticlepeer-review

Abstract

Objective: To study the amount and phenotype of DNA-synthesizing and apoptotic cells during atherogenesis. Methods: Atherosclerotic lesions (n=76), obtained at autopsy (N=6) or during vascular surgery (N=8), were classified [type I-VI; American Heart Association (AHA) classification], immunolabeled with MIB 1 or the TUNEL technique and double stained with cell- type-specific antibodies. Subsequently, the labeled fractions were quantified. Results: In type II-VI lesions, intimal DNA synthesis was increased compared to that of the non-diseased (ND) arterial wall. DNA synthesis peaked in early type II lesions (2.7±0.5 vs. 0.02±0.02% in ND; p<0.05), and declined to 0.7±0.2% in type V lesions (p<0.05). Interestingly, a second peak of DNA synthesis of 1.7±0.1%, was observed in type VI (ruptured plaque) lesions. Double staining revealed that DNA synthesis was mostly confined to the macrophage-derived foam cell (51.9%). In type II lesions, 100.0% of all DNA-synthesizing cells were present in the intimal foam cell-rich area, while in advanced type III, IV and V lesions, DNA synthesis had shifted to the shoulder region (74.8, 78.5 and 68.1%, respectively). In type VI lesions, DNA synthesis was present in the area underlying the plaque rupture (52.7%). Apoptosis was only elevated in advanced type IV, V and VI lesions (0.82±0.1, 0.8±0.1 and 1.1±0.1%, respectively, vs. 0.0±0.0% in ND) and was predominant in the lipid core (90.5% in type IV lesions; 54.2% in type V lesions) or equally divided between the lipid core and the region underlying the plaque rupture (31.8 and 34.6% in type VI lesions). In type III-VI lesions, 50.0, 38.9, 42.6 and 42.8% of the TUNEL-positive cells were macrophages. Conclusions: In stable atherosclerotic lesions, DNA synthesis is an early event, while apoptosis is a late event. Ruptured plaques show a second peak of cell turnover. Lastly, cell turnover is mostly confined to the macrophage-derived foam cell.

Keywords

  • Apoptosis
  • Atherosclerosis
  • Macrophage
  • Proliferation
  • Smooth muscle

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

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