Abstract 11416: Rosuvastatin Improves Efficacy of Transplanted Mesenchymal Stem Cells via Enhanced Activation of JAK2/STAT3 in Infarcted Hearts
Background: Widespread death of implanted cells hampers stem cell therapy for acute myocardial infarction (AMI). We have shown previously that a short-time administration of statins improved survival of mesenchymal stem cells (MSCs) after AMI by creating a better microenvironment. However, the exact mechanism of statins remains unknown.
Methods and results: Female Sprague-Dawley rats (n=200) were randomized to 1 of 5 groups (n=40): control (group 1), rosuvastatin (4mg/kg/d,p.o.,group 2), MSCs transplantation (group 3), rosuvastatin plus MSCs (group 4), and rosuvastatin plus MSCs plus JAK2 inhibitor AG490 (4mg/kg, i.p., once every three days, group 5). AMI was created by ligating the left anterior descending coronary artery; MSCs were injected directly into the myocardium one week after AMI. At 28 days after transplantation, survival of MSCs was 4.5-fold higher in group 4 compared with group 3. M-mode echocardiography indicated that left ventricular end-diastolic diameters (LVEDd) and end-systolic diameters (LVESd) were improved significantly more in group 4 (LVEDd: 7.71±0.25 mm; LVESd:5.54 ±0.26mm) than in the group 3(LVEDd: 8.44±0.32 mm; LVESd: 6.32±0.28, n=8, P<0.01). Moreover, group 4 showed a 29% reduction of fibrosis and a 39% increase of capillary density in the peri-infarct area compared with group 3. Confocal imaging after α-sarcomeric actinin and von Willebrand factor specific immunostaining showed extensive engraftment and cardiovascular differentiation of group 4 compared with group 3 (P<0.01). Furthermore, phosphorylation of JAK2 and STAT3 was significantly increased in the myocardium in group 2 and 4 but not group 3 when compared with control (P<0.05). However, all these effects of rosuvastatin were significantly attenuated by AG490.
Conclusion: Rosuvastatin improves the therapeutic efficacy of MSCs transplantation by activating JAK2/STAT3 pathway and subsequently promoting cell survival and cardiovascular differentiation.
- © 2010 by American Heart Association, Inc.