Abstract 3295: Inhibition of Endogenous Lats2 Prevents Cell Death and Heart Failure Under Pressure Overload
Lats2, a tumor suppressor, is a component of the mammalian Hippo pathway, an evolutionarily conserved signaling pathway regulating organ size and cell death. Lats2 plays an important role in mediating apoptosis and suppression of hypertrophy by Mst1, another component of the
Hippo pathway and a facilitator of heart failure. The present investigation was conducted in order to elucidate the function of endogenous Lats2 in the heart in vivo. Lats2 +/− mice at 5 months of age exhibited a significantly smaller number of TUNEL positive myocytes (0.04 and 0.09%, p<0.05 n=5) than wild type (WT) mice at baseline. Myocyte cross sectional area was significantly greater in Lats2 +/− than in WT mice at 5 months of age (333 and 288 μm2, p<0.05 n=5). These results suggest that endogenous Lats2 promotes apoptosis and inhibits hypertrophy at baseline. Lats2 +/− mice have a smaller number of cardiac myocytes in the heart (9.7×106 and 1.2×107 p<0.05 n=5) due to the fact that myocyte proliferation during the fetal period is suppressed without Lats2. As a result, Heart weight (HW)/body weight (BW) in Lats2+/− became greater than that in WT only after 8 months of age (4.5 vs 4.2 n=4). In order to evaluate the function of Lats2 during pressure overload, Lats2+/− mice were subjected to transverse aortic constriction (TAC). Expression of Lats2 was increased by TAC (4.5 fold). After 4 weeks, left ventricular (LV) end diastolic dimension was smaller (4.0 and 4.8 mm, p<0.05 n=6), LV function was better (EF, 46 and 20%, p<0.05 n=6), and lung congestion (lung weight/BW, 7 and 13, p<0.05 n=6) was less in Lats2+/− than in WT mice. The number of TUNEL positive myocytes (0.08 and 0.12%, p<0.05 n=6) and fibrotic area (5.6 and 15.2%, p<0.05 n=6) were smaller in Lats2 +/− than in WT mice. HW/BW was significantly greater in WT than in Lats2+/− mice (9.1 and 7.3, p<0.05 n=6), suggesting that inhibition of Lats2 attenuates pathological hypertrophy. Since Lats2 has cell autonomous anti-hypertrophic effects, the reduced cardiac hypertrophy in Lats2+/− mice could be secondary to the improved LV function compared to WT mice. In conclusion, endogenous Lats2 mediates apoptosis thereby facilitating pathological hypertrophy in response to pressure overload in the adult heart.
This research has received full or partial funding support from the American Heart Association, National Center.