A combination of secondhand cigarette smoke and Chlamydia pneumoniae accelerates atherosclerosis

ObjectiveSecondhand smoke (SS) induces chronic infection of endothelial cells by Chlamydia pneumoniae (Cpn) in vitro. We investigated the in vivo effect on atherosclerosis following exposure to SS and infection with Cpn both independently and in combination in ApoE−/− mice.Methods and resultsPlaques were largest in the combined SS + Cpn-exposed mice with 12-57% greater cross-sectional area compared with all other groups (P < 0.03). Quantitative RT-PCR (qRT-PCR) from aortic roots revealed a synergistic upregulation of both OX40L (CD134L) and MyD88 in SS + Cpn mice (P < 0.05). This upregulation occurred despite decreased numbers of macrophage, dendritic cell, CD4 T cell and smooth-muscle-cell infiltrates as determined by quantitative IHC and qRT-PCR. To elucidate whether enhanced apoptosis correlated with reduced plaque cellularity, area of Tdt-mediated dUTP nick labeling positive (TUNEL+) cells and expression of key bridging molecules necessary for efferocytosis (Mertk, Tgm2, FasL and C1qa) were examined. In SS + Cpn mice, there was an increase of the area of TUNEL+ cells in plaque cores (P < 0.001) and a downregulation of efferocytosis gene expression (P < 0.05). Systemic expression of cytokines in sera (Luminex) showed no differences between groups, suggesting that focal disease mechanisms within the plaque predominated.ConclusionsThe combination of SS exposure and Cpn infection enhanced atherosclerosis more than either variable did independently by activating inflammatory cells and by promoting growth and maturation of lesions via defective phagocytic clearance and accumulation of apoptotic cells.

► We model the effect on atherosclerosis following exposure to smoke and Chlamydia. ► In combination, the two insults enhance atherosclerosis in ApoE knockout mice. ► They promote inflammation, defective phagocytosis and accrual of apoptotic cells. ► Ultimately, atherosclerotic plaques show advancement in growth and maturation.