Abstract 145: Role Of Mitogen Activated Protein Kinase Phosphatase-1 (MKP-1) In Endotoxin-induced Cardiac Dysfunction
Cardiovascular compromise is central to the development of septic shock and increased mortality. Activation of mitogen-activated protein kinase (MAPK) pathways, NOS2 induction and reactive nitrogen species (RNS) have each been implicated, but their interactions are not defined. MKP-1 is a negative regulator of the MAPK inflammatory signaling and is also known to regulate phosphorylation of phospholamban, influencing intracellular calcium handling in cardiac myocytes. We have previously shown that MKP-1 plays a critical role in suppressing endotoxic shock, but its role in sepsis-related cardiac dysfunction is not established. We tested the hypothesis MKP-1 deficiency causes increased cardiac dysfunction following low-dose LPS, which is related to NOS2 induction and/or RNS formation in vivo. Cardiovascular status was evaluated in 5 week-old wild type (WT) and MKP-1 null (−/−) mice at baseline, 4 h and 24 h after LPS (1.5mg/kg i.p.), by noninvasive methods. Cardiac tissues were collected at 24h and evaluated for prevalence of mast cells, nitric oxide synthase-2 (NOS-2) and protein 3-nitrotyrosine by automated digital image analyses. Basally, the MKP-1−/− mice had increased systemic vascular resistance (SVR) (p<0.05), with no change in cardiac output (CO) or fractional shortening (FS) % when compared to WT. LPS in WT mice caused reductions in BP (p<0.05) and increased heart rate (HR)(p<0.05) at 4h, which returned to baseline at 24h, with no significant change in FS% or CO. In contrast, the MKP-1−/− mice showed significant decreases in CO (p<0.05) and HR (p<0.05) at 4h, which returned to baseline at 24h, and decreases in SVR (p<0.05) and FS% (p<0.001) at 4 hrs, which did not return to baseline after 24h. MKP-1−/− mice showed evidence of acute LV dilation but a less increase in myocardial NOS2 (p<0.01), 3-NT (p<0.001), and mast cell prevalence (p<0.05) following LPS. These data suggest that MKP-1 plays an important role in regulating cardiac function during sepsis and contributes to both inflammatory and calcium regulatory pathways in myocytes. Deficiency of MKP-1 leads to an enhanced impairment of cardiovascular function in response to LPS that is associated with dilated cardiomyopathy but does not appear to be related to NOS2 induction, increased RNS formation.