Aprotinin exacerbates left ventricular dysfunction after ischemia/reperfusion in mice lacking tumor necrosis factor receptor I.
Aprotinin is a serine protease inhibitor with diverse biological effects; until recently, it was utilized in the context of ischemia/reperfusion (I/R). It has been hypothesized that a signaling pathway modulated by aprotinin in the context of I/R is the tumor necrosis factor-alpha receptor (TNFR) pathway. An intact mouse model of I/R (30 min ischemia and 60 min reperfusion) was used and left ventricular (LV) peak + maximal rate of left ventricular (LV) peak pressure (dP/dt) was measured in wild-type mice (WT, C57BL/6; n = 10), WT mice with aprotinin (4 mL/kg; n = 10), transgenic mice devoid of the TNFRI (TNFRI-null; n = 10), and TNFRI-null with aprotinin (n=10). Following I/R, LV peak + dP/dt decreased in both WT groups, but remained similar to baseline values in the TNFRI-null group. In contrast, aprotinin caused a marked reduction in LV peak + dP/dt in the TNFRI-null group following I/R. Soluble plasma TNF levels increased in the WT and TNFRI-null mice with I/R and was reduced with aprotinin. Soluble TNFRI and TNFRII levels, indicative of TNF activation, increased in the WT mice following I/R and remained elevated with aprotinin. Soluble TNFRII levels were increased in the TNFRI-null mice following I/R and remained elevated with aprotinin. The new and unique findings of this study were twofold. First, aprotinin failed to improve LV function after I/R despite a reduction in circulating TNF levels. Second, genetic ablation of TNFRI uncovered a negative inotropic effect of aprotinin. These findings demonstrate that complex biological pathways and interactions are affected with broad spectrum serine protease inhibition, which are relevant to myocardial function in the context of I/R.
Sabbagh
Michel J
MJ
Departments of Anesthesiology and Perioperative Medicine, Medical University of South Carolina, Charleston, SC, USA.
Looper
J Michael
JM
Zavadzkas
Juozas A
JA
Stroud
Robert E
RE
Ford
Rachael L
RL
Rivers
William T
WT
Koval
Christine N
CN
McEvoy
Matthew D
MD
Reeves
Scott T
ST
Spinale
Francis G
FG
D000818:Animals; D007611:Aprotinin / Q000008:administration & dosage*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D023421:Models, Animal; D009206:Myocardium / Q000378:metabolism; D011897:Random Allocation; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000235:genetics*; D015427:Reperfusion Injury / Q000378:metabolism*; D015842:Serine Proteinase Inhibitors / Q000008:administration & dosage*; D014409:Tumor Necrosis Factor-alpha / Q000097:blood / Q000378:metabolism; D018487:Ventricular Dysfunction, Left / Q000378:metabolism*
D047888:Receptors, Tumor Necrosis Factor, Type I; D015842:Serine Proteinase Inhibitors; D014409:Tumor Necrosis Factor-alpha; D007611:Aprotinin