Effects of SOCS2 on Doxorubicin-induced Heart Failure and Cardiomyocyte Apoptosis in Rats by Regulating PI3K/AKT Axis

OBJECTIVE To investigate the effect of suppressor of cytokine signaling 2(SOCS2) on doxorubicin-induced heart failure and cardiomyocyte apoptosis in rats by regulating phosphoinositide 3-kinase(PI3K)/protein kinase B(AKT) signaling pathway.

METHODS Fifty male Sprague-Dawley rats were randomly divided into 5 groups(n=10): control group, doxorubicin model group, SOCS2 low dose group(0.5 mg·kg⁻¹), SOCS2 medium dose group(1.0 mg·kg⁻¹), and SOCS2 high dose group(2.0 mg·kg⁻¹). The doxorubicin model group and SOCS2 low, medium and high dose groups were injected with doxorubicin(2.5 mg·kg⁻¹, once a week for 6 weeks, total dose 15 mg·kg⁻¹) via the tail vein to establish heart failure models, while the control group was injected with an equal volume of normal saline. The SOCS2 low, medium and high dose groups were injected with the corresponding dose of SOCS2 recombinant protein weekly during the 6-week modeling period. The total experimental period was 8 weeks(including a 1−2 week baseline cardiac function measurement and acclimation period). At the end of the 8th week, left ventricular end-diastolic diameter(LVEDD), left ventricular end-systolic diameter(LVESD), fractional shortening(FS), and ejection fraction(EF) were measured by echocardiography. Collagen volume fraction(CVF) and perivascular collagen area(PVCA) were assessed by Masson’s staining. Cardiomyocyte apoptosis rate was detected by TUNEL staining. The expression levels of PI3K and AKT mRNA and protein were detected by RT-qPCR and Western blotting, respectively.

RESULTS Compared with the control group, the LVEDD, LVESD, CVF, PVCA, and cardiomyocyte apoptosis rate of doxorubicin model group were increased, while the level of FS and EF were decreased(P<0.05). Compared with the doxorubicin model group, the SOCS2 low, medium and high groups showed improved cardiac function and fibrosis indices, decreased cardiomyocyte apoptosis rate, and increased expression of PI3K and AKT mRNA and protein, all indicators exhibited a clear dose-response relationship(P<0.05).

CONCLUSION SOCS2 recombinant protein may dose-dependently improve doxorubicin-induced heart failure in rats, reduce myocardial fibrosis and apoptosis by up-regulating the activity of the PI3K/AKT pathway, suggesting that SOCS2 is a potential therapeutic target for drug-induced cardiomyopathy.