Inhibition of histone deacetylase-2 (HDAC2), which is a prohypertrophic factor in the heart, can functionally attenuate cardiac hypertrophy. The present study aimed to investigate whether sphingosine‑1‑phosphate (S1P), which has recently been reported to suppress HDAC2 activity, could ameliorate the cardiac hypertrophic response and improve cardiac function in mice with transverse aortic constriction (TAC), as well as to determine the underlying mechanisms. Briefly, 8‑week‑old male C57BL/6 mice were randomly divided into sham, TAC and TAC + S1P groups; the results indicated that S1P treatment attenuated TAC‑induced cardiac dysfunction. In addition, heart size and the expression levels of fetal cardiac genes were reduced in the TAC + S1P group compared with in the TAC group. Furthermore, in cultured H9c2 cells exposed to phenylephrine, S1P was revealed to decrease cardiomyocyte size and the exaggerated expression of fetal cardiac genes. The present study also demonstrated that S1P had no effect on HDAC2 expression, but it did suppress its activity and increase acetylation of histone H3 in vivo and in vitro. Krüppel‑like factor 4 (KLF4) is an antihypertrophic transcriptional regulator, which mediates HDAC inhibitor‑induced prevention of cardiac hypertrophy; in the present study, KLF4 was upregulated by S1P. Finally, the results indicated that S1P receptor 2 (S1PR2) may be involved in the antihypertrophic effects, whereas the suppressive effects of S1P on HDAC2 activity were independent of S1PR2. In conclusion, the present study demonstrated that S1P treatment may ameliorate the cardiac hypertrophic response, which may be partly mediated by the suppression of HDAC2 activity and the upregulation of KLF4; it was suggested that S1PR2 may also be involved. Therefore, S1P may be considered a potential therapy for the treatment of heart diseases caused by cardiac hypertrophy.

BackgroundThe evidence supporting the use of β‐blockers in patients with acute coronary syndrome after successful percutaneous coronary intervention has been inconsistent and scarce.Methods and ResultsBetween March 1, 2009, and December 30, 2014, a total of 3180 eligible patients with acute coronary syndrome undergoing percutaneous coronary intervention were consecutively enrolled. The primary end point was all‐cause death and the secondary end point was a composite of all‐cause death, nonfatal myocardial infarction, heart failure readmission, and cardiogenic hospitalization. Patients were compared according to the use of β‐blockers at discharge. Compared with the no β‐blocker group, the risk of all‐cause death was significantly lower in the β‐blocker group (hazard ratio [HR], 0.33; 95% CI, 0.17–0.65 [P=0.001]). A consistent result was obtained in multiple adjusted model and propensity score–matched analysis. The use of β‐blockers was also associated with decreased risk of composite of adverse cardiovascular events (HR, 0.47; 95% CI, 0.28–0.81 [P=0.006]), although statistical significance disappeared after multivariable adjustment and propensity score matching. Furthermore, we performed post hoc analysis for the subsets of patients and the results revealed that patients with non–ST‐segment elevation myocardial infarction benefited the most from β‐blocker therapy at discharge (HR, 0.04; 95% CI, 0.00–0.27 [P=0.001]), and the use of <50% of target dose was significantly associated with better outcome compared with no β‐blocker use, rather than ≥50% of target dose.ConclusionsThe administration of relatively low β‐blocker dose is associated with improved clinical outcomes among patients with acute coronary syndrome after successful percutaneous coronary intervention, especially for patients with non‐ST‐segment elevation myocardial infarction.

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