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Apolipoprotein M Improves Survival in Congestive Heart Failure via Enhanced Akt Signaling

2016; Elsevier BV; Volume: 22; Issue: 8 Linguagem: Inglês

10.1016/j.cardfail.2016.06.016

1532-8414

Ali Javaheri, Swapnil V. Shewale, Cecilia Frej, Mingxia Liu, Ken Bedi, Jeff Brandimarto, Anbin Mu, Tao Wang, Christina Y. Chen, Xiucui Ma, Payman Zamani, Benjamin French, Kenneth B. Margulies, Thomas P. Cappola, Benjamin L. Prosser, Abhinav Diwan, Björn Dahlbäck, John S. Parks, Daniel J. Rader,

Lipoproteins and Cardiovascular Health

Background: Apoptosis is an important mechanism that contributes to heart failure (HF) progression. High-density lipoprotein (HDL) protects cardiomyocytes from apoptosis via signaling through the sphingolipid sphingosine-1-phosphate (S1P). Apolipoprotein M (apoM) mediates the physical interaction between S1P and HDL. We hypothesized that apoM levels are associated with improved survival in heart failure patients and that apoM overexpression would improve cardiac function in vivo. Methods and Results: We measured apoM and S1P levels in 212 subjects from the Penn Heart Failure Study (PHFS), a prospective, multi-center observational study. PHFS participants with ischemic cardiomyopathy were propensity matched to those with non-ischemic cardiomyopathy based on age, sex, hypercholesterolemia, and statin use. We found that apoM levels were strongly associated with survival free from cardiac transplantation and left ventricular assist device placement among participants with ischemic and non-ischemic cardiomyopathy (adjusted hazard ratio [95% CI]: 0.86 [0.78, 0.96], P = .009, and 0.85 [0.78, 0.94], P = .001, for each 0.1 micromolar increase in apoM, respectively). To understand the mechanism underlying the association between apoM and survival, we utilized a murine model of hepatic apoM overexpression (apoMTG). apoMTG mice exhibit a 5-fold increase in plasma apoM and HDL-associated S1P. Additionally, apoMTG mice demonstrated improved systolic performance in vivo, and a 40% absolute increase in survival in a model of acute doxorubicin-induced cardiotoxicity. Doxorubicin reduced left ventricular end-diastolic dimension in WT mice, but not apoMTG littermates. In cardiac lysates from apoMTG mice, we observed hyper-phosphorylation of the pro-survival kinase PI3K/Akt, downstream phosphorylation of glycogen synthase kinase 3-beta, and evidence of attenuation of doxorubicin-induced autophagosome accumulation. Ex-vivo treatment of neonatal rat ventricular myocytes with HDL isolated from apoMTG, but not WT mice, decreased doxorubicin-induced caspase activation. Conclusions: ApoM is significantly associated with survival in heart failure patients. This association may be due to improvements in cardiomyocye survival in HF via activation of Akt. ApoM administration should be evaluated as a therapeutic strategy in HF.