Myocardial infarction accelerates atherosclerosis

Abstract

During progression of atherosclerosis, myeloid cells destabilize lipid-rich plaques in the arterial wall and cause their rupture, thus triggering myocardial infarction and stroke. Survivors of acute coronary syndromes have a high risk of recurrent events for unknown reasons. Here we show that the systemic response to ischaemic injury aggravates chronic atherosclerosis. After myocardial infarction or stroke, Apoe-/- mice developed larger atherosclerotic lesions with a more advanced morphology. This disease acceleration persisted over many weeks and was associated with markedly increased monocyte recruitment. Seeking the source of surplus monocytes in plaques, we found that myocardial infarction liberated haematopoietic stem and progenitor cells from bone marrow niches via sympathetic nervous system signalling. The progenitors then seeded the spleen, yielding a sustained boost in monocyte production. These observations provide new mechanistic insight into atherogenesis and provide a novel therapeutic opportunity to mitigate disease progression.

Conflict of interest statement

COMPETING FINANCIAL INTERESTS

Marc S. Sabatine, David A. Morrow and Sabina A. Murphy received grant support from AstraZeneca and GSK. The remaining authors declare no competing financial interests.

Figures

Figure 1. Increased inflammation in atherosclerotic plaques after MI

a, Protease activity by FMT-CT before and 3 weeks after MI. Circles indicate aortic root (n = 10 per group). b, Protease activity in excised aortae by fluorescence reflectance imaging (FRI), expressed as target to background ratio (TBR, n = 10 per group). c, Flow cytometric quantification of myeloid cells and Ly-6Chigh monocytes in aorta (n = 5–9 per group). Dot plots 3 weeks after MI are shown. d, CD11b staining and lesion size (n = 9–10 per group). Scale bar represents 150 μm. Mean ± s.e.m., * P < 0.05, ** P < 0.01.

Figure 2. Elevated levels of progenitor cells in the spleen of apoE−/− mice after MI

a, Quantification for HSPCs, MDPs, and GMPs at different time points after MI (n = 3–15 per group). The gating strategy is shown in Supplementary Fig. 10. b, Number of colony-forming units. Mean ± s.e.m., * P < 0.05, ** P < 0.01.

Figure 3. β3 adrenergic receptor-mediated progenitor release after MI

a, Flow cytometric analyses of HSPC in blood of C57BL/6 mice (n = 6–11 per group). b, Immunostaining for tyrosine hydroxylase (TH). Scale bar represents 10μm. Insets depict low magnification overview. Bar graph shows quantitation of TH+ area (n = 5 per group). c, Expression of HSPC retention factors (relative to Gapdh) in the bone marrow of C57BL/6 mice on day 4 after MI (n = 8 per group). Mean ± s.e.m., * P < 0.05, ** P < 0.01.

Figure 4. Serial intravital imaging of progenitor release from the bone marrow

a, DiD labelled-HSPC Flk2− cells were imaged in the skull bone marrow by intravital microscopy (IVM) before and then again 4 days after MI. DiD labelled-HSPC are white, blood pool red, and bone is blue. The scale bar represents 50 μm. b, Change of HSPC presence between 1st and 2nd IVM session (n = 3 per group). Mean ± s.e.m., * P < 0.05.

Figure 5. Splenic progenitor engraftment after MI

a, qPCR of SCF in spleen (n = 5–6 per group). b, Number of SCF+ cells in spleen of C57BL/6 mice 4 days after MI by immunofluorescence. c, Enumeration of adoptively transferred GFP+ HSPCs on day 4 after MI (n = 8 per group). d, Proliferation of endogenous HSPCs determined by BrdU incorporation (n = 8 per group). e, Paradigm. Mean ± s.e.m., * P < 0.05, ** P < 0.01.