Abstract 1483: The Absence of PI3K γ is Beneficial in a Mouse Model of Myocardial Ischemia/Reperfusion

Abstract

Introduction - Phosphoinositide 3-Kinase gamma (PI3Kγ) is a well-known key enzyme in inflammation pathways. Emerging data demonstrate that PI3Kγ plays a distinct role in cardiomyocytes, but its influence in the setting of myocardial ischemia and reperfusion is still an enigma. To clarify these effects we examined the morphology and contractility of PI3Kγ−/−hearts after ischemia and reperfusion. Methods - PI3Kγ knock out (KO) mice and C57 Bl6 wild type (WT) mice were subjected to 30 minutes of ischemia followed by 3 hours, 1 week and 3 weeks of reperfusion. We therefore reversibly ligated the left anterior descending artery (LAD) in an in vivo model and harvested the myocardium after the defined time of reperfusion. Histological sections were stained with H&E and Masson Trichrome in order to measure the area of infartion and the amount of interstitial fibrosis. Furthermore, Troponin T serum levels were determined and transthoracic echocardiography was performed for measuring the differences in myocardial contractiliy. Results - Comparing PI3Kγ KO mice with WT mice, we found a significant decrement of Troponin T serum levels in the transgenic group 3 hours after reperfusion (0.77±0.28 vs. 1.28±0.48 ng/ml, p<0.001). In addition, a distinct reduction of myocardial infarction was observed in the KO group compared to the WT mice (3 hours: 1.18±0.31 vs. 1.78±0.45 mm 2 , p=0.001; 1 week: 0.88±0.32 vs. 1.29±0.34 mm 2 , p=0.001; 3 weeks: 0.62±0.18 vs. 1.87±0.59 mm 2 , p<0.001). Furthermore, we showed a matching smaller quantity of myocardial fibrosis in the transgenic cohort (1 week: score 1.23±0.6 vs. 2.13±0.74, p=0.005; 3 weeks: score 1.08±0.79 vs. 2±0.71, p=0.014). Fractional shortening (FS) analysis determined by echocardiography revealed significantly enhanced myocardial contractility in PI3Kγ lacking mice after ischemia and reperfusion (1 week: 37.85±7.71 vs. 23.75±8.78 %FS, p=0.007; 3 weeks: 30.67±4.87 vs. 23.7±7.47 %FS, p=0.043). Conclusions - Our data provide the first evidence for the crucial role of PI3Kγ signalling in myocardial ischemia/reperfusion injury: PI3Kγ deficient mice show a significantly better outcome concerning infarction area, Troponin T elevation, scar size, fibrosis, and contractility at all stages of reperfusion (3 hours to 3 weeks).