title: Immunosuppression With FTY720 Reverses Cardiac Dysfunction in Hypomorphic ApoE Mice Deficient in SR-BI Expression That Survive Myocardial Infarction Caused by Coronary Atherosclerosis.
abstract: OBJECTIVE
  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.
  
  
  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.
authors: Departments of *Surgery; and †Medicine, San Francisco VA Medical Center, University of California, San Francisco, San Francisco, CA.
authors: Fu Sang
authors: FS
authors: Luk
authors: Roy Y
authors: RY
authors: Kim
authors: Kang
authors: K
authors: Li
authors: Daniel
authors: D
authors: Ching
authors: David K
authors: DK
authors: Wong
authors: Sunil K
authors: SK
authors: Joshi
authors: Isabella
authors: I
authors: Imhof
authors: Norman
authors: N
authors: Honbo
authors: Holly
authors: H
authors: Hoover
authors: Bo-Qing
authors: BQ
authors: Zhu
authors: David H
authors: DH
authors: Lovett
authors: Joel S
authors: JS
authors: Karliner
authors: Robert L
authors: RL
authors: Raffai
mesh_terms: D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency*; D003324:Coronary Artery Disease / Q000188:drug therapy* / Q000378:metabolism / Q000401:mortality; D059305:Diet, High-Fat / Q000009:adverse effects; D000068876:Fingolimod Hydrochloride / Q000627:therapeutic use*; D005786:Gene Expression Regulation; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D051379:Mice; D008822:Mice, Transgenic; D009203:Myocardial Infarction / Q000188:drug therapy* / Q000378:metabolism / Q000401:mortality; D051122:Scavenger Receptors, Class B / Q000096:biosynthesis*; D015996:Survival Rate / Q000639:trends
chemical_list: D001057:Apolipoproteins E; D007166:Immunosuppressive Agents; C454739:Scarb1 protein, mouse; D051122:Scavenger Receptors, Class B; D000068876:Fingolimod Hydrochloride