Publications

AIMS

We recently reported that immunosuppression with FTY720 improves cardiac function and extends longevity in Hypomorphic ApoE mice deficient in scavenger receptor Type-BI expression, also known as the HypoE/SR-BI(–/–) mouse model of diet-induced coronary atherosclerosis and myocardial infarction (MI). In this study, we tested the impact of FTY720 on cardiac dysfunction in HypoE/SR-BI(–/–) mice that survive MI and subsequently develop chronic heart failure.

METHODS/RESULTS

HypoE/SR-BI(–/–) mice were bred to Mx1-Cre transgenic mice, and offspring were fed a high-fat diet (HFD) for 3.5 weeks to provoke hyperlipidemia, coronary atherosclerosis, and recurrent MIs. In contrast to our previous study, hyperlipidemia was rapidly reversed by inducible Cre-mediated gene repair of the HypoE allele and switching mice to a normal chow diet. Mice that survived the period of HFD were subsequently given oral FTY720 in drinking water or not, and left ventricular (LV) function was monitored using serial echocardiography for up to 15 weeks. In untreated mice, LV performance progressively deteriorated. Although FTY720 treatment did not initially prevent a decline of heart function among mice 6 weeks after Cre-mediated gene repair, it almost completely restored normal LV function in these mice by 15 weeks. Reversal of heart failure did not result from reduced atherosclerosis as the burden of aortic and coronary atherosclerosis actually increased to similar levels in both groups of mice. Rather, FTY720 caused systemic immunosuppression as assessed by reduced numbers of circulating T and B lymphocytes. In contrast, FTY720 did not enhance the loss of T cells or macrophages that accumulated in the heart during the HFD feeding period, but it did enhance the loss of B cells soon after plasma lipid lowering. Moreover, FTY720 potently reduced the expression of matrix metalloproteinase-2 and genes involved in innate immunity-associated inflammation in the heart.

CONCLUSIONS

Our data demonstrate that immunosuppression with FTY720 prevents postinfarction myocardial remodeling and chronic heart failure.

By convention, airborne particles ≤0.1 μm (100 nm) are defined as ultrafine particles (UFPs). UFPs can comprise a large number of particles in particulate matter with aerodynamic diameters ≤2.5 μm (PM). Despite the documented respiratory health effects of PM and concerns that UFPs might be more toxic than larger particular matter, the effects of UFPs on the respiratory system are not well-described. Even less is known about the respiratory health effects of UFPs among particularly vulnerable populations including children. We reviewed studies examining respiratory health effects of UFPs in children and identified 12 relevant articles. Most (8/12) studies measured UFP exposure using central ambient monitors, and we found substantial heterogeneity in UFP definitions and study designs. No long-term studies were identified. In single pollutant models, UFPs were associated with incident wheezing, current asthma, lower spirometric values, and asthma-related emergency department visits among children. Also, higher exhaled nitric oxide levels were positively correlated with UFP dose among children with asthma or allergy to house dust mites in 1 study. Multivariate models accounting for potential co-pollutant confounding yielded no statistically significant results. Although evidence for a relationship between UFPs and children's respiratory is accumulating, the literature remains inconclusive. Interpretation of existing data is constrained by study heterogeneity, limited accounting for UFP spatial variation, and lack of significant findings from multi-pollutant models.