title: The immunosuppressant FTY720 prolongs survival in a mouse model of diet-induced coronary atherosclerosis and myocardial infarction.
abstract: FTY720, an analogue of sphingosine-1-phosphate, is cardioprotective during acute injury. Whether long-term FTY720 affords cardioprotection is unknown. Here, we report the effects of oral FTY720 on ischemia/reperfusion injury and in hypomorphic apoE mice deficient in SR-BI receptor expression (ApoeR61(h/h)/SRB1(-/- mice), a model of diet-induced coronary atherosclerosis and heart failure. We added FTY720 (0.3 mg·kg(-1)·d(-1)) to the drinking water of C57BL/6J mice. After ex vivo cardiac ischemia/reperfusion injury, these mice had significantly improved left ventricular (LV) developed pressure and reduced infarct size compared with controls. Subsequently, ApoeR61(h/h)/SRB1(-/-) mice fed a high-fat diet for 4 weeks were treated or not with oral FTY720 (0.05 mg·kg(-1)·d(-1)). This sharply reduced mortality (P < 0.02) and resulted in better LV function and less LV remodeling compared with controls without reducing hypercholesterolemia and atherosclerosis. Oral FTY720 reduced the number of blood lymphocytes and increased the percentage of CD4+Foxp3+ regulatory T cells (Tregs) in the circulation, spleen, and lymph nodes. FTY720-treated mice exhibited increased TGF-β and reduced IFN-γ expression in the heart. Also, CD4 expression was increased and strongly correlated with molecules involved in natural Treg activity, such as TGF-β and GITR. Our data suggest that long-term FTY720 treatment enhances LV function and increases longevity in mice with heart failure. These benefits resulted not from atheroprotection but from systemic immunosuppression and a moderate reduction of inflammation in the heart.
authors: Cardiology Section, Medical Service, VA Medical Center, San Francisco and the University of California, San Francisco.
authors: Guanying
authors: G
authors: Wang
authors: Surgical Service, VA Medical Center, San Francisco and the Department of Surgery, University of California, San Francisco.
authors: Roy Y
authors: RY
authors: Kim
authors: Cardiology Section, Medical Service, VA Medical Center, San Francisco and the University of California, San Francisco.
authors: Isabella
authors: I
authors: Imhof
authors: Cardiology Section, Medical Service, VA Medical Center, San Francisco and the University of California, San Francisco.
authors: Norman
authors: N
authors: Honbo
authors: Surgical Service, VA Medical Center, San Francisco and the Department of Surgery, University of California, San Francisco.
authors: Fu Sang
authors: FS
authors: Luk
authors: Surgical Service, VA Medical Center, San Francisco and the Department of Surgery, University of California, San Francisco.
authors: Kang
authors: K
authors: Li
authors: Surgical Service, VA Medical Center, San Francisco and the Department of Surgery, University of California, San Francisco.
authors: Nikit
authors: N
authors: Kumar
authors: Cardiology Section, Medical Service, VA Medical Center, San Francisco and the University of California, San Francisco.
authors: Bo-Qing
authors: BQ
authors: Zhu
authors: Surgical Service, VA Medical Center, San Francisco and the Department of Surgery, University of California, San Francisco.
authors: Delphine
authors: D
authors: Eberlé
authors: Surgical Service, VA Medical Center, San Francisco and the Department of Surgery, University of California, San Francisco.
authors: Daniel
authors: D
authors: Ching
authors: Cardiology Section, Medical Service, VA Medical Center, San Francisco and the University of California, San Francisco.
authors: Joel S
authors: JS
authors: Karliner
authors: Surgical Service, VA Medical Center, San Francisco and the Department of Surgery, University of California, San Francisco.
authors: Robert L
authors: RL
authors: Raffai
mesh_terms: D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics*; D002316:Cardiotonic Agents / Q000008:administration & dosage / Q000494:pharmacology; D003324:Coronary Artery Disease / Q000188:drug therapy* / Q000503:physiopathology; D059305:Diet, High-Fat / Q000009:adverse effects; D004195:Disease Models, Animal; D000068876:Fingolimod Hydrochloride; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000494:pharmacology; D007249:Inflammation / Q000188:drug therapy / Q000209:etiology / Q000503:physiopathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009203:Myocardial Infarction / Q000188:drug therapy* / Q000503:physiopathology; D015428:Myocardial Reperfusion Injury / Q000188:drug therapy / Q000503:physiopathology; D011409:Propylene Glycols / Q000008:administration & dosage / Q000494:pharmacology*; D013110:Sphingosine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D015996:Survival Rate; D050378:T-Lymphocytes, Regulatory / Q000378:metabolism; D013997:Time Factors; D016212:Transforming Growth Factor beta / Q000378:metabolism; D016277:Ventricular Function, Left / Q000187:drug effects
chemical_list: D001057:Apolipoproteins E; D002316:Cardiotonic Agents; D007166:Immunosuppressive Agents; D011409:Propylene Glycols; D016212:Transforming Growth Factor beta; D000068876:Fingolimod Hydrochloride; D013110:Sphingosine