Farnesyltransferase (FTase) is one of the three enzymes in the prenyltransferase group that catalyzes most prenylation reactions and has been proposed as one component of acute inflammation. Endotoxemia was induced in male Wistar rats weighing 300-340 g by lipopolysaccharide (LPS) injection (10 mg/kg BW IV rout via the rat tail vein). Hemodynamic evaluation was performed 4-6 h post-LPS injection by measuring left ventricular end-diastolic pressure, dP/dtmax and myocardial tissue was histologically assessed to analyze macrophage infiltration and cellular damage. Left ventricular function was significantly impaired in the LPS-treated rats, as demonstrated by dP/dtmax (5579±213 vs. 2929±246 mmHg, ctrl vs. LPS; P=0.002) and ejection fraction (61% vs. 23%, ctrl vs. LPS; P=0.0035). LPS was significantly correlated with prominent myocardial cell injury characterized by the increased plasma cardiac troponin-I (cTn-I) and upregulation of proinflammatory cytokines. Furthermore, rats pretreated with FTase inhibitor (Tipifarnib 15 mg/kg BW, IV rout via the rat tail vein) shortly before LPS administration improved myocardial function, dP/dtmax (2929±246 vs. 4125±126 mmHg, LPS vs. Tipifarnib; P<0.05) and ejection fraction (23% vs. 41%, LPS vs. Tipifarnib; P<0.05). The proinflammatory cytokines level, cTn-I level and macrophage accumulation are reduced after neutralized the LPS by FTase inhibitor P<0.05. These data suggest that FTase is a new potential molecular target to improved myocardial function in sepsis.
Novel route to chaetomellic acid A and analogues: Serendipitous discovery of a more competent FTase inhibitor
