MicroRNA-377 Mediates Cardiomyocyte Apoptosis Induced by Cyclosporin A.

Cyclosporin A (CsA) is a potent immunosuppressant that has wide clinical applications for autoimmune disorders and prevention of rejection in organ transplantation. However, its liver, kidney, and heart toxicity has limited its use. In this study, we investigated the mechanism by which CsA induced cardiomyocyte apoptosis. Through microarray analysis, we found that the expression of microRNA (miR)-377 was regulated by CsA. Ectopic overexpression of miR-377 led to increased apoptosis in cardiomyocytes, as evidenced by an increased number of apoptotic cells, increased levels of proapoptotic proteins, decreased levels of antiapoptotic proteins, and elevated caspase pathway activity. We also found that miR-377 was required for CsA-induced apoptosis, because inhibition of miR-377 expression markedly reduced the ability of CsA to induce cardiomyocyte apoptosis. In addition, we identified XIAP and NRP2 as direct targets for miR-377. The expression levels of these 2 antiapoptotic proteins were negatively regulated by miR-377, as well as by CsA both in vitro and in vivo. Our data suggested that CsA induced cardiomyocyte apoptosis through the miR-377-XIAP/NRP2 axis.

The effects of atorvastatin on pulmonary arterial hypertension and expression of p38, p27, and Jab1 in rats.

Statins have recently come under evaluation for the treatment of pulmonary arterial hypertension (PAH). The aim of this study was to examine the effects of atorvastatin on the clinical manifestations and expression of p38, p27 and Jab1 using a rat PAH model. Ninety-six male Wistar rats were divided into control (receiving no surgical treatment), vehicle and treatment groups, among which the last two groups underwent left pneumonectomy and were then treated with monocrotaline (MCT, 60 mg/kg). Both control and vehicle groups subsequently received saline, and the treatment group received atorvastatin (20 mg/kg) by stomach catheter. Rats were sacrificed, and mean pulmonary arterial pressure (mPAP) and right ventricle hypertrophy index (RVHI) were measured. The expression of p38, p27, and Jab1 was evaluated by immunohistochemistry and Western blotting. At 28 days, mPAP and RVHI and expression levels of Jab1 and p38 in the vehicle group were significantly higher than those in the treatment and control groups. However, the expression of p27 was lowest in the vehicle group among the three groups. Atorvastatin reduced PAP and RVHI in the rat PAH model, decreased expression of p38 and Jab1 but increased expression of p27.