Inhibition of farnesyl pyrophosphate synthase improves pressure overload induced chronic cardiac remodeling.

Farnesyl pyrophosphate synthase (FPPS) is a key enzyme in the mevalonate pathway. In our previous studies, we find that inhibition of FPPS attenuates angiotensin II-induced cardiac hypertrophy and fibrosis by suppressing RhoA while FPPS and Ras are up-regulated in pressure overload rats. In this study, we evaluate the effects and mechanisms of FPPS inhibition in pressure overload mice. Male FPPS-small interfering RNA (SiRNA) transgenic (Tg) mice and non-transgenic littermate control (NLC) were randomly divided into suprarenal abdominal aortic constriction (AAC) group and sham operation group. 12 weeks following AAC, mice were sacrificed by cervical dislocation. Histological and echocardiographic assessments showed that inhibition of FPPS improved chronic cardiac remodeling which was induced by AAC. The reductions of Ras farnesylation and GTP-Ras, as well as their downstream extracellular signal-related kinases 1/2 (ERK1/2) expression were observed in the heart of Tg-AAC mice compared with NLC-AAC mice, along with the reduction of fetal gene expression. We provide here important experimental evidence that inhibition of FPPS improves AAC induced chronic cardiac remodeling and fibrosis by the reduction of farnesylated Ras and the downregulation of Ras-ERK1/2 pathway.

Mild hypothermia in improving multiple organ dysfunction after cardiac arrest.

BACKGROUND: Resuscitation after cardiac arrest (CA) with a whole-body ischemia-reperfusion injury causes brain injury and multiple organ dysfunction (MODS). This study aimed to determine whether mild systemic hypothermia could decrease multiple organ dysfunctions after resuscitation from cardiac arrest. METHODS: The patients who had been resuscitated after cardiac arrest were reviewed. During the resuscitation they had been assigned to undergo therapeutic hypothermia (target temperature, 32°C to 34°C, measured in the rectum) over a period of 24 to 36 hours or to receive standard treatment with normothermia. Markers of different organ injury were evaluated for the first 72 hours after recovery of spontaneous circulation (ROSC). RESULTS: At 72 hours after ROSC, 23 patients in the hypothermia group for whom data were available had favorable neurologic, myocardial, hepatic and pulmonic outcomes as compared with 26 patients in the normothermia group. The values of renal function were not significantly different between the two groups. However, blood coagulation function was badly injured in the hypothermia group. CONCLUSION: In the patients who have been successfully resuscitated after cardiac arrest, therapeutic mild hypothermia can alleviate dysfunction after resuscitation from cardiac arrest.