Abstract 902: Lysosomal Integral Membrane Protein-2 is a Novel Component of the Intercalated Disc and Essential for a Compensatory Hypertrophic Response to Pressure-Overload
The intercalated disc (ID) is emerging as a crucial structure in the heart. A comprehensive array study in failure-prone cardiac hypertrophy identified the lysosomal integral membrane protein-2 (LIMP-2) as a novel modulator of ID function. To establish the functional role of LIMP-2, we infused Angiotensin II (AngII) or saline for 4 weeks in LIMP-2 knockout mice (LIMPKO) and wild type mice. LIMPKO developed normally under baseline conditions. However, chronic AngII infusion in LIMPKO caused significant left ventricular (LV) fibrosis (15.0±6.0% in LIMPKO vs 1.8±0.1% in controls; P<0.002) and heart failure, as shown by a disturbed response to dobutamin (p<0.005). Surprisingly, in LIMPKO, hypertrophic response to AngII was attenuated (13.7±0.1% in LIMPKO vs 30.2±0.1% in controls; P<0.01), despite comparable induction of BNP. AngII increased individual myocyte area in control but not in LIMPKO hearts, which was paralleled by a diminished induction of α-smooth muscle actin. In cultured myocytes, stretch increased LIMP-2 expression (P<0.02) and in exercise induced physiological hypertrophy, LIMP-2 was also increased (2.1-fold, P<0.04). These results show that LIMP-2 is necessary to develop compensatory hypertrophy. Immunohistochemistry and immunoelectron microscopy revealed that LIMP-2 resides on plasma membranes of cardiac myocytes. In addition, AngII disturbed cadherin localization in LIMP-2 knockout mice. Immunoprecipitation and confocal microscopy in human hearts confirmed the interaction between LIMP-2 and cadherin at the ID. RNAi mediated knock-down of LIMP-2 in cardiac myocytes decreased the interaction between cadherin and beta-catenin, indicating a disturbed ID structure. Taken together, this newly uncovered LIMP-2/cadherin axis strongly suggests that LIMP-2 is an important component and modulator of the intercalated disc. Absence of LIMP-2 disturbs the ability of the ID to respond appropriately to increased mechanical loading, and attenuates a normal hypertrophic response which induces adverse cardiac remodeling. We speculate that the LIMP-2/cadherin axis and related integrity of the ID is vital for the healthy, adaptive component of the hypertrophic response to mechanical loading.