Abstract 3622: PTEN Inactivation Promotes Cardiomyocyte Proliferation Following Ischemia Injury
PTEN is a dual lipid and protein phosphatase that antagonizes PI3K signaling events in different cell types and we have recently showed that conditional knockout of PTEN in adult myocytes protects heart against ischemia/reperfusion injury. To investigate the underlying mechanisms of PTEN mediated signaling in long term tissue repair in response to cardiac injury, we characterize the impact of PTEN inactivation on cardiomyocyte proliferation. Cardiac specific inactivation of PTEN (CKO-PTEN) is achieved via tamoxifen induced Cre-loxP mediated DNA recombination in adult mice. After 3 weeks tamoxifen injection, there is no significant difference in cardiac function as well as heart size between CKO-PTEN heart and control. CKO-PTEN resulted in elevated PI3K activity and AKT phosphroylation. In response to Ischemia/Reperfusion (30min/120min) challenge in the Langendorff-preparation, CKO-PTEN hearts have significantly better function recovery and significant reduction in infarct size compared with control, along with less apoptosis positive cardiomyocytes. The expressions of p-ERK and BCL-2 are significant higher after Ischemia/Reperfusion in CKO-PTEN hearts; while there are no remarkable differences at basal compared with litter mate controls. After 2 weeks myocardial infarction (MI) by permanent ligation of left anterior descending aorta, despite remarkable decrease in cardiac functions in CKO-PTEN and control mice relative to basal, there was no significant difference between CKO-PTEN and control groups. However, immunohistochemistry study revealed a trend of increase in BrdU and Ki-67 positive cardiomycytes in the CKO-PTEN hearts relative to Control hearts at basal state. At two weeks post-MI, a significant increase in the number of BrdU and Ki-67 positive myocyte was observed in the remote regions distant from the infacted tissue in CKO-PTEN hearts compared to control hearts. These data indicated that inhibiting of PTEN induces PI3K-AKT signaling and promotes short-term cardio-protection and long-term proliferation of myocytes even in uninjured region. Therefore, targeting PTEN may provide a new approach for cardiac protection against ischemia reperfusion injury.
This research has received full or partial funding support from the American Heart Association, National Center.